Submissions for variant NM_007294.4(BRCA1):c.2758G>A (p.Val920Ile)

gnomAD frequency: 0.00001  dbSNP: rs80357361

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031069	SCV001161495	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	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 = 0.000285
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047959	SCV000075972	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000222489	SCV000273051	benign	Hereditary cancer-predisposing syndrome	2014-12-01	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.
Counsyl	RCV000031069	SCV000488472	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001281724	SCV000512296	likely benign	not provided	2020-02-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16267036, 15385441)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281724	SCV000600301	likely benign	not provided	2020-08-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222489	SCV000910945	benign	Hereditary cancer-predisposing syndrome	2016-09-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798029	SCV002043435	uncertain significance	Breast and/or ovarian cancer	2019-07-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001705614	SCV002070608	uncertain significance	not specified	2018-05-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000222489	SCV002538155	likely benign	Hereditary cancer-predisposing syndrome	2021-06-04	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000031069	SCV004815655	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001705614	SCV005395844	likely benign	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2758G>A (p.Val920Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250896 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2758G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported in the literature. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8850G>T, p.Lys2950Asn; NHGRI BIC Database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in assessing homology-dependent recombination assays (Bouwman_2020). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). The following publication was ascertained in the context of this evaluation (PMID: 32546644). ClinVar contains an entry for this variant (Variation ID: 37488). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP)	RCV000031069	SCV000053665	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-07-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031069	SCV000144535	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001281724	SCV001905832	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705614	SCV001929026	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758608	SCV005360369	likely benign	BRCA1-related disorder	2024-08-26	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).