Submissions for variant NM_007294.4(BRCA1):c.3952A>G (p.Ile1318Val)

dbSNP: rs397509121

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480977	SCV000568410	uncertain significance	not provided	2021-02-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4071A>G; Observed in individuals with a family history of breast and/or ovarian cancer (Arnold 1999, Meindl 2002).; This variant is associated with the following publications: (PMID: 10502781, 11802209, 12457999, 28277317)
Ambry Genetics	RCV000509595	SCV000607980	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing	The p.I1318V variant (also known as c.3952A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3952. The isoleucine at codon 1318 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in studies of families with hereditary breast and ovarian cancer (Arnold N et al. Hum. Mutat. 1999; 14(4):333-9; Meindl A et al. Int. J. Cancer 2002 Feb; 97(4):472-80). 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.
Color Diagnostics, LLC DBA Color Health	RCV000509595	SCV001359358	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1318 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one suspected hereditary breast and ovarian cancer family (PMID: 10502781, 11802209). 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.
Invitae	RCV001339859	SCV001533635	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1318 of the BRCA1 protein (p.Ile1318Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10502781, 12457999, 34178674). ClinVar contains an entry for this variant (Variation ID: 55058). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000480977	SCV002050162	uncertain significance	not provided	2021-04-02	criteria provided, single submitter	clinical testing	The BRCA1 c.3952A>G; p.Ile1318Val variant (rs397509121) is reported in the literature in at least two individuals affected with hereditary breast/ovarian cancer (Arnold 1999, Meindl 2002). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 1318 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.54). Due to limited information, the clinical significance of the p.Ile1318Val variant is uncertain at this time.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509595	SCV003847610	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	RCV004554671	SCV004788207	uncertain significance	BRCA1-related disorder	2024-02-20	criteria provided, single submitter	clinical testing	The BRCA1 c.3952A>G variant is predicted to result in the amino acid substitution p.Ile1318Val. This variant was reported in individuals with a personal or family history of breast and/or ovarian cancer (Meindl et al. 2002. PubMed ID: 11802209; Fanale et al. 2021. PubMed ID: 34178674). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to missense variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as uncertain or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55058/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000480977	SCV001905787	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000480977	SCV001958354	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000480977	SCV001974761	likely benign	not provided		no assertion criteria provided	clinical testing