Submissions for variant NM_000059.4(BRCA2):c.1769T>G (p.Phe590Cys)

gnomAD frequency: 0.00001  dbSNP: rs80358459

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043879	SCV000071892	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130772	SCV000185665	likely benign	Hereditary cancer-predisposing syndrome	2020-10-06	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.
Counsyl	RCV000077265	SCV000488000	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000486075	SCV000566611	likely benign	not provided	2021-03-26	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; A published in vitro functional assay suggests that this variant is able to rescue cell lethality (Mesman 2018); Observed in at least one individual with breast or ovarian cancer (Azzollini 2016); This variant is associated with the following publications: (PMID: 25348012, 11929857, 29988080, 24817641, 27062684, 32854451, 29684080)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486075	SCV000887759	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35402282 (2022), 34178674 (2021), 32854451 (2020)), and Cowden Syndrome/Cowden Syndrome-like Bannayan-Riley Ruvalcaba Syndrome (PMID: 29684080 (2018)). Published functional studies have reported that this variant does not have a deleterious effect on BRCA2 protein function (PMID: 29988080 (2018)). The frequency of this variant in the general population, 0.000012 (3/248932 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000130772	SCV000911109	likely benign	Hereditary cancer-predisposing syndrome	2017-09-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780024	SCV000917027	uncertain significance	not specified	2018-09-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1769T>G (p.Phe590Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 244108 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1769T>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer who was indicated to carry another pathogenic variant, although the variant was not specified (Azzollini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in normal activity using multiple independent measures namely, complementation by BRCA2 variants of the cell lethal phenotype imposed by Cre-mediated loss of Brca2; HDR capacity, as measured by the repair of I-Sce1 induced double strand breaks (DSBs); and Cisplatin sensitivity of BRCA2 variants (Meman_2018). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798227	SCV002042457	uncertain significance	Breast and/or ovarian cancer	2019-05-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130772	SCV002533257	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-04	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130772	SCV003851625	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000077265	SCV000109062	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077265	SCV000145928	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000077265	SCV004228377	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS3(Strong)+BP1(Strong)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)