Submissions for variant NM_000059.4(BRCA2):c.109T>G (p.Ser37Ala)

dbSNP: rs876661275

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000215744	SCV000279956	uncertain significance	not provided	2016-03-02	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.109T>G at the cDNA level, p.Ser37Ala (S37A) at the protein level, and results in the change of a Serine to an Alanine (TCA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 c.337T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser37Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser37Ala occurs at a position that is not conserved and is located in the PALB2 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ser37Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206592	SCV001377906	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-10	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 37 of the BRCA2 protein (p.Ser37Ala). ClinVar contains an entry for this variant (Variation ID: 234881). 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. 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.
Ambry Genetics	RCV002450656	SCV002738327	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-19	criteria provided, single submitter	clinical testing	The p.S37A variant (also known as c.109T>G), located in coding exon 2 of the BRCA2 gene, results from a T to G substitution at nucleotide position 109. The serine at codon 37 is replaced by alanine, an amino acid with 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.