Submissions for variant NM_007294.4(BRCA1):c.3713C>G (p.Pro1238Arg)

dbSNP: rs28897688

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562256	SCV000661085	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-07	criteria provided, single submitter	clinical testing	The p.P1238R variant (also known as c.3713C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3713. The proline at codon 1238 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001342448	SCV001536381	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1238 of the BRCA1 protein (p.Pro1238Arg). This variant is present in population databases (rs28897688, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033, 21520333). ClinVar contains an entry for this variant (Variation ID: 54974). 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%. 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.
GeneDx	RCV003125888	SCV003803370	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3832C>G; This variant is associated with the following publications: (PMID: 15235020)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000562256	SCV003849996	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).
Color Diagnostics, LLC DBA Color Health	RCV000562256	SCV004360219	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 1238 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251286 chromosomes 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.
All of Us Research Program, National Institutes of Health	RCV000112162	SCV004817762	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 1238 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251286 chromosomes 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	RCV004689436	SCV005185156	uncertain significance	not specified	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3713C>G (p.Pro1238Arg) 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 4e-06 in 251286 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3713C>G has been reported in the literature. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 15235020). ClinVar contains an entry for this variant (Variation ID: 54974). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003125888	SCV005626081	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	The BRCA1 c.3713C>G (p.Pro1238Arg) variant has been reported in the published literature in individuals undergoing hereditary cancer testing (PMID: 31853058 (2020), 15235020 (2004)), and described to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000004 (1/251286 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112162	SCV000144846	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112162	SCV000297605	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-12-21	no assertion criteria provided	clinical testing