Submissions for variant NM_139076.3(ABRAXAS1):c.659C>T (p.Ala220Val)

gnomAD frequency: 0.00005  dbSNP: rs568225415

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000807129	SCV000947168	uncertain significance	not provided	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 220 of the ABRAXAS1 protein (p.Ala220Val). This variant is present in population databases (rs568225415, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 27270457). ClinVar contains an entry for this variant (Variation ID: 651714). 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.
Ambry Genetics	RCV004028279	SCV003860178	uncertain significance	not specified	2024-12-03	criteria provided, single submitter	clinical testing	The p.A220V variant (also known as c.659C>T), located in coding exon 7 of the FAM175A gene, results from a C to T substitution at nucleotide position 659. The alanine at codon 220 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004028279	SCV005185808	uncertain significance	not specified	2024-05-30	criteria provided, single submitter	clinical testing	Variant summary: FAM175A c.659C>T (p.Ala220Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 246722 control chromosomes, predominantly at a frequency of 0.00021 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.659C>T has been reported in the literature in one individuals affected with Breast Cancer but also in one control subject (Renault_2016). 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: 27270457). ClinVar contains an entry for this variant (Variation ID: 651714). Based on the evidence outlined above, the variant was classified as uncertain significance.