Submissions for variant NM_000059.4(BRCA2):c.7006C>T (p.Arg2336Cys)

gnomAD frequency: 0.00009  dbSNP: rs431825347

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132214	SCV000187296	likely benign	Hereditary cancer-predisposing syndrome	2018-03-09	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000082966	SCV000196000	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000588307	SCV000210410	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast and/or ovarian cancer (Levanat et al., 2012; Alemar et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7234C>T; This variant is associated with the following publications: (PMID: 31143303, 29541205, 29161300, 22366370, 32297440, 37129948, 32467295)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476201	SCV000549540	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2336 of the BRCA2 protein (p.Arg2336Cys). This variant is present in population databases (rs431825347, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 22366370; internal data). This missense change has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 96845). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31143303; internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855635	SCV000695020	uncertain significance	not specified	2024-10-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7006C>T (p.Arg2336Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Wangensteen_2019). The variant allele was found at a frequency of 1.8e-05 in 1604526 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.7006C>T has been reported in the literature in individuals with a personal and/or family history of Hereditary Breast and Ovarian Cancer and pancreatic ductal adenocarcinoma (Levanat_2012, Alemar_2017, Militello_2023, Bhai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported at our laboratory, BRCA1 c.5324T>G(p.Met1775Arg), providing supporting evidence for a benign role. At least one publication reports experimental evidence that this variant has no impact on protein function (Sahu_2023). The following publications have been ascertained in the context of this evaluation (PMID: 29161300, 34326862, 18844490, 22366370, 37725113, 37713444, 31143303). ClinVar contains an entry for this variant (Variation ID: 96845). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588307	SCV001469447	uncertain significance	not provided	2024-10-15	criteria provided, single submitter	clinical testing	The BRCA2 c.7006C>T (p.Arg2336Cys) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 22366370 (2012), 29161300 (2017), 33471991 (2021), 38509102 (2024)). The variant has also been reported in an unaffected individual (PMID: 32467295 (2020)). Splicing studies have shown that this variant results in normal splicing patterns and unaltered transcripts (PMID: 31143303 (2019)). The frequency of this variant in the general population, 0.00012 (3/24854 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000132214	SCV001735733	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2336 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 a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_005905) and in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 22366370, 29161300). This variant has been identified in 4/279248 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798283	SCV002043411	uncertain significance	Breast and/or ovarian cancer	2021-01-21	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153360	SCV003843660	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000082966	SCV004844345	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2336 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 a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_005905) and in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 22366370, 29161300). This variant has been identified in 4/279248 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)	RCV000082966	SCV000115040	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-10-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732660	SCV005347880	uncertain significance	BRCA2-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The BRCA2 c.7006C>T variant is predicted to result in the amino acid substitution p.Arg2336Cys. This variant was reported in individuals with a personal or family history of breast and ovarian cancer, but family or functional studies were not reported to help assess the pathogenicity of this variant (Levanat et al. 2012. PubMed ID: 22366370; Alemar et al. 2017. PubMed ID: 29161300). In vitro splicing studies found that this variant did not alter splicing (Wangensteen T et al 2019. PubMed ID: 31143303). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/96845/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.