Submissions for variant NM_007294.4(BRCA1):c.1974G>C (p.Met658Ile)

gnomAD frequency: 0.00005  dbSNP: rs55678461

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082658	SCV000075682	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000047669	SCV000167247	benign	not specified	2014-02-28	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.
Ambry Genetics	RCV000130602	SCV000185477	likely benign	Hereditary cancer-predisposing syndrome	2018-12-11	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	RCV000111744	SCV000488131	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-01-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000047669	SCV000593683	uncertain significance	not specified	2016-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047669	SCV000698903	likely benign	not specified	2023-03-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1974G>C (p.Met658Ile) 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 6e-05 in 251078 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (6e-05 vs 0.001), allowing no conclusion about variant significance. c.1974G>C has been reported in the literature in individuals affected with Hereditary Breast and/or Ovarian Cancer (example, Judkins_2005, Lu_2012, Li_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA1 c.66_67delAG (c.68_69del), p.Glu23fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments with a majority consensus leaning towards benign (n=1)/likely benign(n=5) (VUS, n=3). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000130602	SCV000902675	likely benign	Hereditary cancer-predisposing syndrome	2015-06-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590433	SCV001133507	likely benign	not provided	2022-08-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590433	SCV001371126	likely benign	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130602	SCV002538074	likely benign	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000047669	SCV002551024	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130602	SCV003849593	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).
PreventionGenetics, part of Exact Sciences	RCV003905008	SCV004719067	likely benign	BRCA1-related condition	2020-09-22	criteria provided, single submitter	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111744	SCV000144266	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000047669	SCV000591360	benign	not specified		no assertion criteria provided	clinical testing	The p.Met658Ile variant has been previously identified in the BIC (n=27 as unknown clinical importance), LOVD (n=1) and Exome Server (n=3 out of 13001 chromosomes) databases and appears to be a low frequency variant. This variant is listed in the dbSNP database (ID#:rs55678461) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. It was reported once in the literature in an in silico study where conservation and biophysical properties of the variant were analyzed and used for classification. The variant was predicted to be neutral (Abkevich_2004_15235020). This residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. However, our lab has previously identified this variant in one individual who also had a second pathogenic variant and increasing the likelihood this variant is benign. Myriad genetics has reported this variant as a polymorphism in Jan 2010. In summary, based on the above information this variant is classified as a benign variant.