Submissions for variant NM_007294.4(BRCA1):c.1396C>T (p.Arg466Trp)

gnomAD frequency: 0.00001  dbSNP: rs80356964

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132353	SCV000187442	likely benign	Hereditary cancer-predisposing syndrome	2017-04-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Genetic Services Laboratory, University of Chicago	RCV000502109	SCV000593671	uncertain significance	not specified	2017-03-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132353	SCV000682958	likely benign	Hereditary cancer-predisposing syndrome	2021-08-13	criteria provided, single submitter	clinical testing
Invitae	RCV001485675	SCV001690121	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132353	SCV002538020	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-21	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149590	SCV003838907	uncertain significance	Breast and/or ovarian cancer	2021-08-26	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132353	SCV003851323	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).
GeneDx	RCV001353504	SCV003923990	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual from a family with suspected hereditary breast and ovarian cancer (Capone et al., 2018); Also known as 1515C>T; This variant is associated with the following publications: (PMID: 15385441, 26272908, 24413733, 12872252, 29061375, 31131967, 15343273, 32377563, 29884841, 31911673)
PreventionGenetics, part of Exact Sciences	RCV003415748	SCV004113616	uncertain significance	BRCA1-related condition	2023-09-11	criteria provided, single submitter	clinical testing	The BRCA1 c.1396C>T variant is predicted to result in the amino acid substitution p.Arg466Trp. This variant was reported in an unknown sample from a validation study of a BRCA1 and BRCA2 NGS-based test (Table S1 in Capone et al 2017. PubMed ID: 29061375). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41246152-G-A). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant has been reported in ClinVar as likely benign and uncertain by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/37410/). Of note, a different variant impacting the same amino acid (p.Arg466Gly) was documented in a patient with breast cancer (Abulkhair et al. 2018. PubMed ID: 30199306, variant referred to as c.1396C>G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Sharing Clinical Reports Project (SCRP)	RCV000030991	SCV000053583	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030991	SCV000144083	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353504	SCV000591327	likely benign	not provided		no assertion criteria provided	clinical testing	The p.Arg466Trp variant was not identified in the literature but was identified in dbSNP (ID: rs80356964) “With other, untested allele”, UMD (1X as an unclassified variant), and the BIC database (4X with unknown clinical importance). It was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports), increasing the likelihood this variant does not have clinical significance. The p.Arg466 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
BRCAlab, Lund University	RCV000030991	SCV004244128	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing