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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 32-41

Spectrum of germline BRCA mutations in hereditary breast and ovarian cancer syndrome in Indian population: A central reference laboratory experience

Department of Integrated Oncopathology, Metropolis Healthcare Ltd., Mumbai, Maharashtra, India

Date of Submission11-Nov-2019
Date of Decision15-Dec-2019
Date of Acceptance20-Jan-2020
Date of Web Publication24-Feb-2020

Correspondence Address:
Kirti Chadha
Unit No. 409 to 416, 4th Floor, Commercial Building A, Kohinoor City, Near Kohinoor Mall, Kirol Road, Kurla-W, Mumbai - 400 070, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_101_19

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Introduction: There is a growing need for BRCA1/BRCA2 mutation frequencies among hereditary breast and ovarian carcinoma (HBOC) cases, specifically determined on the grounds of personal and family history profiles in the Indian population. The current study was intended to identify BRCA1/2 mutation frequency and spectrum in Indian women fulfilling the National Comprehensive Cancer Network criteria.
Methods: One hundred and sixty unrelated women were screened for germline variations in BRCA1 and BRCA2 genes by sequencing. The variants were classified as pathogenic or benign on the basis of American College of Medical Genetics (ACMG) guidelines.
Results: Of 160 women screened for BRCA mutations, 51 (31.9%) carried a pathogenic variant in BRCA1 (n = 36) or BRCA2 (n = 15) gene. An increased frequency of mutation was seen in women with a personal history of breast or ovarian cancer (34.5%) in comparison to unaffected family members (25%). A spectrum of 34 different pathogenic variants (20 in BRCA1 and 14 in BRCA2) was identified in 51 cases. This included a novel variant c.3683_3684dup in BRCA1 which was categorized as a pathogenic variant. The variant c.68_69delAG in BRCA1 was identified in 12/51 positive cases and appears to be the hotspot mutation in the Indian population. In addition, 11 different missense variants were identified in 10 of the study participants and were categorized as variants of unknown clinical significance (VUS) based on the ACMG guidelines. Of these, three of the variants (c.389A>C in BRCA1 and c.3179G>A and c.10124G>T in BRCA2) were unreported in the published literature.
Conclusion: The prevalence of pathogenic variants in the Indian HBOC cohort is high and is similar to other Indian studies. The spectrum of BRCA variants is also diverse, and it is very important to correctly classify them as pathogenic, VUS, or benign. We reinforce the importance of complete BRCA gene screening in the index case, followed by genetic counseling and targeted mutation analysis in other at-risk family members.

Keywords: BRCA1, BRCA2, hereditary breast and ovarian cancer, variant of uncertain significance

How to cite this article:
Chheda P, Pande S, Dama T, Vinarkar S, Chanekar M, Limaye S, Shah N, Chadha K. Spectrum of germline BRCA mutations in hereditary breast and ovarian cancer syndrome in Indian population: A central reference laboratory experience. Cancer Res Stat Treat 2020;3:32-41

How to cite this URL:
Chheda P, Pande S, Dama T, Vinarkar S, Chanekar M, Limaye S, Shah N, Chadha K. Spectrum of germline BRCA mutations in hereditary breast and ovarian cancer syndrome in Indian population: A central reference laboratory experience. Cancer Res Stat Treat [serial online] 2020 [cited 2022 Jul 1];3:32-41. Available from: https://www.crstonline.com/text.asp?2020/3/1/32/279065

  Introduction Top

The most common cancer among Indian women is breast cancer with an incidence of 25.8 and mortality of 12.7/100,000 women.[1] Almost 5%–10% of these are likely to have hereditary breast and ovarian cancer (HBOC) syndrome, and a majority of such cases (85%) are known to be associated with loss-of-function variants in breast cancer susceptibility genes, BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185).[2],[3] Genetic testing in these BRCA1 and BRCA2 genes has thus become a crucial part of clinical decision-making for women with a strong family background of breast and ovarian cancers and is important for preventive counseling. The lifetime risk in BRCA1- and BRCA2-mutation carriers for developing breast cancer is about 45%-80%, while that of ovarian cancer is >40% and >20% for BRCA-1 mutation carriers and BRCA2-mutation carriers respectively.[4],[5],[6],[7],[8] Besides breast and ovarian cancers, BRCA1/2 mutations have been associated with several cancers, the most common being pancreas, prostate, and melanoma.[9] Poly (ADP-ribose) polymerases, also called PARP inhibitors, are a new class of chemotherapeutic agents that can target cancers with defective DNA-damage repair. The U.S. Food and Drug Administration and European EMA have approved PARP inhibitors, such as olaparib, for the treatment of BRCA1/ 2 mutation-positive ovarian cancers.[10] Recent Phase III trials demonstrated a 3-month progression-free survival improvement with PARP inhibitors in comparison to single-agent chemotherapy in patients with metastatic breast cancer with mutated germline BRCA. PARP inhibitors, however, seem less effective in metastatic breast cancer patients with wild-type BRCA than in those with BRCA-mutated platinum-sensitive recurrent ovarian cancer. This is probably due to biologic heterogeneity and low somatic BRCA mutation rate in breast cancer.[11]

Testing of BRCA1 and BRCA2 variants in high-risk individuals and families is of utmost importance, and it focuses on identification of the most frequent variants – single-base substitutions or deletions or insertions of one or more bases that result either in premature protein chain termination or in loss of function. Such variants that are found throughout the coding regions and at the splice junctions of BRCA1/ 2 account for 10%–50% of the germline variants in HBOC families.[12] Large genomic rearrangements (LGRs) of BRCA1/ 2 have also been detected in HBOC families, though in a smaller proportion (3%–6%).[13],[14] These LGRs, however, are reported to be present at a higher frequency of 10%–30% in certain populations, such as Dutch, Italian, and Greek.[15],[16],[17],[18]

There is a significant variation in BRCA1/ 2 mutation type and frequency with regard to race/ethnicity, as well as geographical location. Founder mutations with relatively higher frequency have been identified in certain populations, for example, one variant in BRCA2 ( 6174delT) and two variants (185delAG, 5382insC) in BRCA1 are present at a very high frequency (~2%) in the Ashkenazi Jewish population.[19],[20] Similarly, BRCA2 founder mutation, 999delTCAAA has been reported at a carrier frequency of 0.4%–0.6% in Icelandic population.[21] The contribution and prevalence of these high-risk variants in the Indian HBOC families are relatively unexplored barring a few studies.[3],[21],[22],[23],[24],[25],[26],[27],[28],[29] With a view to identify the mutation spectrum and to contribute toward Indian-specific BRCA1/ 2 data, we analyzed 160 breast and/or ovarian cancer cases for variants in both the genes.

BRCA1/ 2 testing was performed by the 'gold standard' Sanger sequencing, which is technologically reliable with simple workflow and is widely available. However, of late, it has been replaced in clinical laboratories by next-generation sequencing (NGS) technology, which offers high-throughput analysis in a cost-effective manner.[3],[30] Multiplex ligation-dependent probe amplification (MLPA) is usually employed for the detection of LGRs.[31],[32],[33]

  Materials and Methods Top

Study subjects

BRCA1/ 2 mutation screening data of women subjects (cancer affected cases or family members) referred to our laboratory from January 2014 to September 2019 were retrospectively analyzed. All the women underwent pre-test counseling wherein they were informed about the significance and outcome of molecular genetic screening. Detailed personal and family history was obtained, and written informed consent was taken from all the study participants. The study protocol (Project No. MP-01-2018; [Supplementary Appendix 1]: Study Protocol) was approved by 'Conscience Independent Ethics Committee' in November 2018, and the study was conducted in compliance with the principles of the Declaration of Helsinki. The study was not registered in a public clinical trials registry such as 'The Clinical Trials Registry-India.'

Inclusion criteria

Of 291 women who underwent pre-test genetic counseling, 160 unrelated women participants residing across India and fulfilling National Comprehensive Cancer Network (NCCN) criteria (version 3.2019)[34] for genetic testing of HBOC were included in the study [Table 1].
Table 1: Segregation of study participants with respect to National Comprehensive Cancer Network criteria for genetic risk evaluation

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Overall, 116 women were affected with cancer (breast cancer n = 73, ovarian cancer n = 43) and 44 women were unaffected at the time of BRCA1/ 2 mutation screening but had ≥1 family member with HBOC. The overall mean age of the 160 screened female patients was 46.3 years (standard deviation [SD], 12.6 years).

Mutation detection

BRCA1 and BRCA2 complete gene analysis was carried out by Sanger sequencing for identification of single-nucleotide variations and small insertion–deletions for the initial 86 cases. With technology advancement, the remaining 74 cases were analyzed by NGS. Genomic DNA was extracted from EDTA whole blood by standard procedure using Qiagen QIAmp DNA mini kit.

Sanger sequencing

The coding exons and exon/intron splice junctions of BRCA1/ 2 genes were polymerase chain reaction (PCR) amplified using primer pairs described in BIC database.[35] A total of 78 PCR reactions (32 for BRCA1 and 46 for BRCA2) were set up for each of the patients. This was followed by sequencing using Big Dye Terminator v3.1 Cycle Sequencing Kit on 3500 Dx Genetic Analyzer; Applied Biosystems. To identify the variants, the patient sequences were aligned to the reference sequences (BRCA1 - NM_007294.3; BRCA2 - NM_000059.3) available in NCBI Genbank database using the BioEdit Sequence Alignment software (BioEdit v7.1.11, Ibis Biosciences, Carlsbad, CA).[36]

Next-generation sequencing

Genomic DNA was enzymatically fragmented, and regions of interest were selectively enriched using capture probes targeted against coding regions of the BRCA1 and BRCA2 genes, including 10 bp of flanking intronic sequences. Libraries were generated with Illumina compatible adaptors and sequenced on an Illumina platform with minimum coverage of ×20 for every amplicon.

The variants were described as per human genome variation society nomenclature (http://www.hgvs.org/mutnomen) and classified as deleterious (Class 5 – pathogenic or Class 4 – likely pathogenic), variant of unknown clinical significance (VUS, Class 3), likely benign (Class 2), and benign (Class 1) according to the American College of Medical Genetics (ACMG) guidelines.[37] The clinical relevance of the identified variant 'was also indicated in the ClinVar and/or BIC database, National Center for Human Genome Research, NIH, http://research.nhgri.nih.gov/bic/.[35],[38] In addition, in silico analysis tools such as PolyPhen-2 (Polymorphism Phenotyping v2) and MutationTaster were used to predict the deleterious nature of uncommon missense variants.[39],[40]

Statistical analysis

The data were analyzed using IBM SPSS Statistics software v. 21.0 (Armonk, NY, USA). Descriptive statistics for continuous variables were presented as “mean ± SD” and for categorical variables as percent frequency. Statistical significance was evaluated for the association between the categorical variables using Chi-square test and Fisher's exact test. P < 0.05 was considered statistically significant.

  Results Top

A total of 291 women underwent pre-test genetic counseling; 160 women fulfilled the NCCN criteria and were included in the retrospective study. Thirty-six women did not want to proceed with genetic testing, and the remaining 95 women were excluded from retrospective data analysis on the basis of NCCN guidelines [Figure 1]. Of 160 women screened for BRCA1/ 2 mutations, 116 were cancer-affected cases of which 73 of them had a personal history of breast cancer and 43 had ovarian cancer. Remaining 44 women were themselves unaffected during genetic screening but had a family history of cancer, suggestive of BRCA mutation screening. Overall, of the 160 women who underwent BRCA1/ 2 mutation screening test by sequencing method, 51 (31.87%) of them showed the presence of deleterious variants (Class 4 and 5) in BRCA1 or BRCA2 genes. Higher positivity was seen for BRCA1 in comparison to BRCA2 ( 36/51, 70.58% vs. 15/51, 29.4%). The prevalence of pathogenic variant was 34.48% (40 cases) when cancer-affected women (n = 116) were taken into consideration, while among cancer-unaffected women with HBOC family history (n = 44), the prevalence was 25.0% (11 cases). Of 116 cancer-affected cases, the prevalence of BRCA1/ 2 pathogenic variants in breast cancer cases (23/73 – 31.50%) was lower than ovarian cancer cases (17/43 – 39.53%). Further, the number of BRCA1-positive cases was comparatively much higher than BRCA2 mutations in ovarian cancer patients (14 - BRCA1, 3 - BRCA2) than in breast cancer cases (14 - BRCA1, 9 - BRCA2); however, the results were not statistically significant (P = 0.142).
Figure 1: Workflow of patient selection for the study

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Spectrum of BRCA1/2 pathogenic mutations

A spectrum of 34 different pathogenic variants was identified in 51 cases – 20 in BRCA1 and 14 in BRCA2 [Table 2] and [Table 3]. Among 20 BRCA1 variants, 13 frameshift, five nonsense, and two splice site variants were observed. Similarly, in BRCA2, 10 frameshift, one nonsense, one missense, and two splice site pathogenic variants were detected.
Table 2: List of deleterious mutations (Class 4 and 5) in BRCA1 gene

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Table 3: List of deleterious mutations (Class 4 and 5) in BRCA2 gene

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[Figure 2] and [Figure 3] show 34 different pathogenic variants identified in BRCA1 and BRCA2 genes, respectively. The most common variant was c.68_69delAG (p. Glu23Valfs*17) in BRCA1 and was identified in 12 cases, followed by c.5074+1G>A mutation in BRCA1 which was found in three of the cases. Variant - c.4183C>T, c.4035delC, c.516delA in BRCA1 and c.8488-1G>A in BRCA2 were identified in two cases each. The remaining pathogenic variants were identified only once each in the study population. We also came across a novel frameshift variant c.3683_3684dup (p. Leu1229Thrfs*7) which has not been previously reported in the literature. This variant which was identified in a case of ovarian cancer was classified as a Class 5 - pathogenic mutation-based on available evidence as per the ACMG guidelines. Further, several common benign polymorphic variants were observed in the study cohort (data not shared).
Figure 2: Schematic diagram of the positions of the deleterious mutations identified in the BRCA1 gene

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Figure 3: Schematic diagram of the positions of the deleterious mutations identified in the BRCA2 gene

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Variant of uncertain significance identified

Besides deleterious mutations and common benign polymorphisms, a total of 11 different variants of conflicting pathogenicity or VUS (Class 3 variants) were identified in 10 of 160 (6.25%) women. Of these, four distinct VUS were found in BRCA1 and seven in BRCA2 [Table 4]. Three of the patients showed the presence of two VUS each. In addition, two of the variants, c.7505G>A and c.9728C>T, were found in two of the study participants each. All VUS were missense mutations located within the exonic regions, eight of which were previously reported in the ClinVar database. The remaining three were novel variants unreported in the literature -c.389A>C (p. Tyr130Ser) in BRCA1 and c.3179G>A (p. Ser1060Asn) and c.10124G>T (p. Ser3375Iso) in BRCA2. Although Tyr130Ser variant has not been reported earlier, different variations at the same position, c.389A>T, p. Tyr130Phe, and c.389A>G, p. Tyr130Cys, have been reported in the ClinVar database as VUS. In silico analysis using PolyPhen2 and MutationTaster software suggested that all the exonic variants were likely tolerated, except for three of them that were classified as disease-causing (c.389A>C and c.5107T>C in BRCA1 and c.6935A>T in BRCA2). Further, of these 12 cases showing the presence of unknown variants, one case showed co-occurrence of a pathogenic variant. This case showed the presence of p. Gly800Valfs*10 deleterious variant along with two VUS – p. Ser1060Asn (novel variant) and c.10120A>G. This fact suggests lower possibility of these variants to be disease-causing mutations with deleterious function.
Table 4: List of Unknown Variants (Class 3) in BRCA1 and BRCA2 genes

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  Discussion Top

Several therapeutic options and risk-reducing strategies are now available for breast and/or ovarian cancer patients and at-risk family members with pathogenic germline variant in BRCA1/2 genes. Additionally, negative findings on targeted mutation analysis in relatives of known carriers reduce anxiety related to cancer risk, and general population screening can be followed thereafter. We investigated BRCA1/BRCA2 mutations in Indian women fulfilling the NCCN criteria for genetic testing of breast and/or ovarian cancer.

The study comprised BRCA1/ 2 gene sequencing to detect point mutations and small insertions/deletions. We observed deleterious mutations in BRCA1/2 in 31.87% (51/160) of cases. Of the 51 BRCA positives, BRCA1 mutation was detected in 70.58% (36/51) cases and BRCA2 in 29.4% (15/51) cases. In addition, higher proportion of positivity was seen in cancer-affected probands (34.48%) in comparison to unaffected probands with HBOC family history (25.0%). Earlier studies on women of Indian origin with early-onset breast cancer have reported positivity in the range of 2.9% to 50% for BRCA1/BRCA2 mutations.[22],[23],[24],[25],[27],[41],[42] Another Indian study tested 14 genes associated with HBOC and identified mutations in 30.1% (n=304) cases, majority (84.9%) of which were detected in the BRCA1/ 2 genes and few (15.1%) were detected in non-BRCA genes.[3] A recent study in the North Indian population has documented mutation frequency of 30.1% (62/206) for the presence of Class 3, 4, and 5 variants.[30] Our study has documented slightly higher frequency (31.87%) of deleterious mutations by sequencing technology alone (MLPA-based large gene rearrangement was not part of the study) in comparison to other Indian studies. Globally, variable frequency of BRCA1/ 2 mutation has been reported ranging from 10% to 50%.[12],[33],[43],[44],[45] Studies also support the fact that multigene testing by NGS can yield additional genomic information and increases the rate of mutation detection of risk-associated genes in HBOC.[3],[46]

The prevalence of mutation in BRCA1 ( 70.58%) was much higher than BRCA2 ( 29.4%) in our study as well as several other studies.[3],[43] This frequency of BRCA1 mutations increases even further when standalone ovarian cancer cases are considered. In the present study, ovarian cancer cases showing BRCA1 mutations were almost five times higher than the ones showing BRCA2 mutations (BRCA1 mutations – 14/23, BRCA2 mutations – 3/23). Similar observation was found in previous studies wherein BRCA1 was 4–8 times more common than BRCA2 in ovarian cancer cases.[46],[47],[48]

The spectrum of BRCA1/2 mutations is quite diverse as seen from our data as well as other global studies.[49] In the present study, we have identified 34 different variants in 51 subjects [Table 2] and [Table 3]. The most common mutation was c.68_69delAG (popularly known as 185delAG) in BRCA1 seen in 12 cases, c.5074+1G>A in BRCA1 found in three of the cases, and variants such as c.4183C>T, c.4035delC, c.516delA in BRCA1 and c.8488-1G>A in BRCA2 found twice in the study cohort. Both the BRCA1 variants –c.68_69delAG (common mutations found in Ashkenazi Jews) and c.5074+1G>A – have been previously reported at a higher frequency in other Indian studies.[3],[25],[41],[50] There is another Indian study that specifically concentrated on the identification of c.68_69delAG (185delAG) and c.5946delT (6174delT) founder mutations in 231 breast cancer cases from Eastern India and did not find them in any of the subjects.[51] Except for a few common variants such as c.68_69delAG and c.5266dupC (5382insC) which are noted in most of the populations studied, the global spectrum of BRCA1/ 2 variants is quite diverse. Apart from the known founder mutations, other variants identified at relatively higher frequencies in specific ethnic groups/geographic locations can be combined together to form a targeted panel and offered in those specific populations. However, in our population, although certain variations (c.68_69delAG and c.5074+1G>A in BRCA1) were seen in relatively higher proportion, more studies involving larger number of cases are required to come up with an Indian-specific hotspot mutation panel as a first tier testing. In addition, in case of genetic analysis in at-risk individuals where a pathogenic mutation is already identified in the family, targeted or single-site mutation testing by Sanger sequencing rather than BRCA1/2 complete gene analysis reduces the testing cost to one-tenth.

We came across 11 different VUS in 10 of the 160 patients (6.25%) with majority of them in BRCA2 ( 8 variants). The frequency of VUS reported in different studies across the globe varies widely and depends on the population being analyzed. It ranges from 5% to 6% in probands of European ancestry in the USA to about 21% in African-American populations.[52] The possibility and outcome of having a VUS result should be discussed with the patient during genetic counseling session before the patient decides to proceed with germline mutation analysis. This highlights the importance of pre- and post-test genetic counseling by a qualified genetic counselor. Consideration of PARP inhibitor therapy in patients with VUS is also a matter of concern. In a study carried out by Chevrier et al., 11 patients showed the presence of VUS, which were further classified as potentially benign or deleterious based on allele frequency and Protein Variation Effect Analyzer analysis.[53] VUS predicted to be pathogenic showed better response or PFS than the benign variants when the patients were put on PARP inhibitor therapy.[53] However, larger studies are required to validate the same.

  Conclusion Top

Our findings of BRCA1/2 mutation profiling on selected HBOC cohort of Indian origin shows that the prevalence of pathogenic variants is quite high and is similar to that reported in other Indian and international studies. Although a heterogeneous spectrum of variants in BRCA1 and BRCA2 is noted, the variants c.68_69delAG and c.5074+1G>A appear to be the most common mutations in the Indian population. Identification of BRCA1/2 mutation in carriers will assist in the management and surveillance focusing on reducing the risk of breast and ovarian cancer, genetic counseling, and testing of other at-risk relatives. Knowledge of BRCA1/2 status in newly diagnosed breast cancer patients may influence surgical decision-making.


We thank Ms. Ankita Chaurasia for assistance with data preparation.

Financial support and sponsorship

All the authors were employed by Metropolis Healthcare Ltd.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]


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