Submissions for variant NM_007294.4(BRCA1):c.4111G>C (p.Gly1371Arg)

dbSNP: rs774593602

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165223	SCV000215937	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.G1371R variant (also known as c.4111G>C), located in coding exon 10 of the BRCA1 gene, results from a G to C substitution at nucleotide position 4111. The glycine at codon 1371 is replaced by arginine, an amino acid with dissimilar properties. One study detected this alteration in 0/1398 patients with unilateral breast cancer and 1/705 patients with contralateral breast cancer (Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688766	SCV000816390	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1371 of the BRCA1 protein (p.Gly1371Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 185744). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000165223	SCV000906470	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1371 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with breast cancer (PMID: 20104584, 21520273). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.1026 and 1.4557, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779865	SCV000916734	uncertain significance	not specified	2018-03-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4111G>C (p.Gly1371Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 243394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4111G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237751	SCV002009446	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003237751	SCV004224362	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	PM2
GeneDx	RCV003237751	SCV005327359	uncertain significance	not provided	2023-11-20	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); Also known as 4230G>C; This variant is associated with the following publications: (PMID: 29884841, 20104584, 31131967, 32377563, 15343273, 22737296, 21520273)