Submissions for variant NM_000059.4(BRCA2):c.8805G>A (p.Met2935Ile)

dbSNP: rs730881568

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160157	SCV000210484	uncertain significance	not provided	2014-01-10	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8805G>A at the cDNA level, p.Met2935Ile (M2935I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Met2935Ile 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. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is highly variable throughout evolution and is located in the DNA-binding domain (Borg 2010). In silico analyses predict this variant to have a benign effect on protein structure and function. The currently available evidence about this variant does not allow us to predict whether BRCA2 Met2935Ile is a pathogenic variant or benign variant, and it is therefore classified as having unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243762	SCV001416943	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-11-01	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182255). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 2935 of the BRCA2 protein (p.Met2935Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine.