Submissions for variant NM_139076.3(ABRAXAS1):c.941A>G (p.Asn314Ser)

gnomAD frequency: 0.00014  dbSNP: rs376489465

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000587773	SCV000951512	uncertain significance	not provided	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 314 of the ABRAXAS1 protein (p.Asn314Ser). This variant is present in population databases (rs376489465, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ABRAXAS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496543). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ABRAXAS1 protein function with a negative predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174778	SCV001338107	likely benign	not specified	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: FAM175A c.941A>G (p.Asn314Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 1614000 control chromosomes, predominantly at a frequency of 0.00023 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in FAM175A causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (3.1e-05). c.941A>G has been reported in the literature among cases and controls in a study investigating monogenic causes of non-BRCA familial breast cancer as a case-control study (example, Li_2021). 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 has been ascertained in the context of this evaluation (PMID: 34117267). ClinVar contains an entry for this variant (Variation ID: 496543). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV001174778	SCV003860101	likely benign	not specified	2024-03-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.