Submissions for variant NM_007294.4(BRCA1):c.1202G>A (p.Gly401Glu)

dbSNP: rs397507184

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130767	SCV000185660	likely benign	Hereditary cancer-predisposing syndrome	2024-04-15	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	RCV000030979	SCV000488367	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539447	SCV000635781	benign	Hereditary breast ovarian cancer syndrome	2025-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130767	SCV000688321	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 401 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24249303, 28111427, 28364669, 29215753, 30652428). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293586	SCV001482198	uncertain significance	not specified	2021-02-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1202G>A (p.Gly401Glu) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 273334 control chromosomes, specifically at a frequency of 0.00031 (7/11241) in a Japanese female control group (Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1202G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, mainly in Japanese or Korean populations and likely with overlapping patients within each cohort (Nakamura_2013, Arai_2018, Liu_2019, Nakagomi_2018, Ryu_2017, Momozawa_2018). These reports do not provide strong evidence of causality and do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three labs classified the variant as a VUS while one classified the variant as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002472941	SCV002770238	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Observed in individuals with breast and/or ovarian cancer, and also observed in unaffected controls (Nakamura et al., 2015; Park et al., 2017; Ryu et al., 2017; Arai et al., 2018; Momozawa et al., 2018; Nakagomi et al., 2018; Liu et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1321G>A; This variant is associated with the following publications: (PMID: 29884841, 28364669, 30652428, 32377563, 20215511, 10426999, 9582019, 9926942, 15343273, 28111427, 29176636, 29215753, 30287823, 24249303)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130767	SCV003846107	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).
Fulgent Genetics, Fulgent Genetics	RCV005016302	SCV005647177	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-02-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000030979	SCV000053571	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-09-22	no assertion criteria provided	clinical testing