Submissions for variant NM_007294.4(BRCA1):c.67G>C (p.Glu23Gln)

dbSNP: rs372047427

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000510068	SCV000608005	likely benign	Hereditary cancer-predisposing syndrome	2021-12-31	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.
Invitae	RCV001224557	SCV001396762	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 23 of the BRCA1 protein (p.Glu23Gln). This variant is present in population databases (rs372047427, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 21918854, 32380732, 32856854). ClinVar contains an entry for this variant (Variation ID: 441390). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 25823446, 30209399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269115	SCV001448358	uncertain significance	not specified	2020-11-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.67G>C (p.Glu23Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250924 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.67G>C has been reported in the literature in individuals with a personal or family history of breast and/or ovarian cancer (Keshavarzi_2012, Chowdhury_2020, Incorvaia_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. An in vitro study that assessed the effect of the variant in a haploid human cell line whose survival is dependent on intact BRCA1 function, demonstrated no damaging effect of this variant (Findlay 2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Brotman Baty Institute, University of Washington	RCV001076497	SCV001242263	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV001076497	SCV004244204	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing