Submissions for variant NM_000059.4(BRCA2):c.3085A>G (p.Met1029Val)

gnomAD frequency: 0.00001  dbSNP: rs80358553

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484779	SCV000566190	uncertain significance	not provided	2015-04-04	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3085A>G at the cDNA level, p.Met1029Val (M1029V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). Using alternate nomenclature, this variant would be defined as BRCA2 3313A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Met1029Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Met1029Val occurs at a position that is not conserved across species and is located in the first BRC repeat region (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Met1029Val is a pathogenic variant or benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001361254	SCV001557223	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1029 of the BRCA2 protein (p.Met1029Val). This variant is present in population databases (rs80358553, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51396). 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 BRCA2 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.
Ambry Genetics	RCV002321539	SCV002608837	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-01	criteria provided, single submitter	clinical testing	The p.M1029V variant (also known as c.3085A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3085. The methionine at codon 1029 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002321539	SCV003851672	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000083096	SCV004174871	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1029 of the BRCA2 protein (p.Met1029Val). This variant is present in population databases (rs80358553, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51396).This amino acid position is not well conserved ( PhyloP =0.43). In addition, this alteration is predicted to be tolerated by in silico analysis. 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 .
MGZ Medical Genetics Center	RCV003607212	SCV004543887	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR
All of Us Research Program, National Institutes of Health	RCV000083096	SCV004845106	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1029 of the BRCA2 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 1 individual affected with breast cancer and in 1 unaffected individual (PMID: 31837001, 33471991; Leiden Open Variation Database DB-ID BRCA2_008028). This variant has been identified in 2/250064 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.
Sharing Clinical Reports Project (SCRP)	RCV000083096	SCV000115170	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083096	SCV000146167	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-03-30	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083096	SCV004243599	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing