Submissions for variant NM_007294.4(BRCA1):c.4115G>A (p.Cys1372Tyr)

gnomAD frequency: 0.00001  dbSNP: rs55848034

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195393	SCV000076459	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1372 of the BRCA1 protein (p.Cys1372Tyr). This variant is present in population databases (rs55848034, gnomAD 0.01%). This missense change has been observed in individual(s) with unspecified cancer (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 55105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887, 30765603). 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.
Ambry Genetics	RCV000132315	SCV000187401	likely benign	Hereditary cancer-predisposing syndrome	2019-03-25	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.
GeneDx	RCV001284399	SCV000210166	likely benign	not provided	2021-11-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15235020, 12955082, 16267036, 28873162, 28781887, 29280214, 15343273, 22737296)
Color Diagnostics, LLC DBA Color Health	RCV000132315	SCV000909278	likely benign	Hereditary cancer-predisposing syndrome	2017-11-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284399	SCV001470177	uncertain significance	not provided	2020-03-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798247	SCV002043444	uncertain significance	Breast and/or ovarian cancer	2020-06-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281742	SCV002570848	uncertain significance	not specified	2022-07-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4115G>A (p.Cys1372Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248774 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4115G>A has been reported in the literature in individual(s) affected with cancer, including Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005, Mandelker_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with pathogenic variants has been reported in one sample (BRCA1 c.3607C>T, p.Arg1203X; BRCA2 c.5946delT, p.Ser1982ArgfsX22; UMD), providing supporting evidence for a benign role. In a transcriptional activation assay, the variant was found to have approximately 84% the activity of the wildtype BRCA1 protein, suggesting it has minimal impact on protein function (Woods_2016). Using a computational tool that incorporated the results of this functional assay to predict the likelihood of pathogenicity, the variant was classified as likely not pathogenic/non-pathogenic (Woods_2016, Fernandes_2019). Six assessments for this variant have been submitted to ClinVar after 2014 (likely benign n=3, VUS n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112263	SCV000144985	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	RCV000112263	SCV000591491	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Cys1372Tyr variant was identified in the literature in one in silico study, where the authors found it to be neutral or of little clinical significance (Abkevich 2004). The variant was also reported in dbSNP (ID: rs55848034) “with unknown allele”, LOVD, BIC (3X as a variant with unknown clinical importance), and once in UMD as an unclassified variant. Within the UMD record it was reported to co-occur with a known pathogenic mutation in BRCA2 (c.5946delT, p.Ser1982ArgfsX22), increasing the likelihood that the p.Cys1372Tyr variant does not have clinical significance. In addition, computation analyses (PolyPhen2, SIFT, Align GVGD) do not suggest a high likelihood of impact to the protein and the p.Cys1372 residue is poorly conserved through evolution, with the variant amino acid (Tyr) present in other species (including orangutan, macaque, mouse, dog, and opossum), increasing the likelihood that this may be a benign variant. Although the variant occurs outside of the splicing consensus sequence, three in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume 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.