Submissions for variant NM_000059.4(BRCA2):c.9106C>G (p.Gln3036Glu)

gnomAD frequency: 0.00001  dbSNP: rs202155613

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000074559	SCV000108644	uncertain significance	not provided	2019-05-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18627636, 27157322, 30934991, 29684080, 23165508, 29138572, 29875142, 26689913, 33314489, 31825140)
Ambry Genetics	RCV000223314	SCV000276148	likely benign	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000031795	SCV000383801	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000344086	SCV000383802	uncertain significance	Fanconi anemia complementation group D1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000031795	SCV000488164	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000289162	SCV000549747	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223314	SCV000910983	likely benign	Hereditary cancer-predisposing syndrome	2023-02-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271381	SCV002556186	uncertain significance	not specified	2022-06-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9106C>G (p.Gln3036Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.2e-05 in 291048 control chromosomes (gnomAD, Li_2015, Dong_2021, Sullivan_2021). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.9106C>G has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (e.g. Thirthagiri_2008, Kwong_2016, Li_2018, Wang_2019, Sullivan_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function: complementation assays using mouse Embryonic Stem cells lacking brca2 transfected with the human variant protein showed that there was no reduction in viability, and no increased sensitivity to DNA damage (Sullivan_2021). This demonstrated that the variant had no damaging effect on protein function and could fully rescue the brca2 null cells. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Baylor Genetics	RCV002250496	SCV004211900	uncertain significance	Familial cancer of breast	2023-10-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031795	SCV004846124	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 3036 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 18627636, 30078507) but also in controls (PMID: 30078507). This variant has been identified in 11/280278 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000031795	SCV000054403	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-06-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031795	SCV000147540	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250496	SCV002520849	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only