Submissions for variant NM_007294.4(BRCA1):c.1924G>C (p.Asp642His)

gnomAD frequency: 0.00001  dbSNP: rs80357344

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111734	SCV000244310	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000014
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047642	SCV000075655	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162974	SCV000213462	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000430192	SCV000518067	likely benign	not specified	2015-07-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics, part of Exact Sciences	RCV000679686	SCV000806904	likely benign	not provided	2017-07-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162974	SCV000906650	likely benign	Hereditary cancer-predisposing syndrome	2017-12-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679686	SCV001133505	likely benign	not provided	2018-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000430192	SCV001623213	likely benign	not specified	2021-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1924G>C (p.Asp642His) 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 was absent in 251006 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1924G>C has been reported in the literature as a VUS in individuals undergoing clinical genetic testing for breast cancer (example Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Subsequently, studies utilizing multifactorial probability models have reported this variant with a neutral outcome based on a low posterior probability of pathogenicity (example, Lindor_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as likely benign. Based on peer consensus and the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000430192	SCV002064764	uncertain significance	not specified	2020-09-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.1924G>C, in exon 10 that results in an amino acid change, p.Asp642His. This sequence change does not appear to have been previously described in patients with BRCA1-related disorders. This sequence change was absent in the gnomAD database (dbSNP rs80357344). The p.Asp642His change affects a moderately conserved amino acid residue located in the DNA binding domain of the BRCA1 protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp642His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp642His change remains unknown at this time.
Sema4, Sema4	RCV000162974	SCV002538069	likely benign	Hereditary cancer-predisposing syndrome	2022-02-19	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000111734	SCV004818254	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111734	SCV000144250	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing