Submissions for variant NM_000057.4(BLM):c.934T>G (p.Ser312Ala)

gnomAD frequency: 0.00005  dbSNP: rs372454889

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543241	SCV000623358	uncertain significance	Bloom syndrome	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 312 of the BLM protein (p.Ser312Ala). This variant is present in population databases (rs372454889, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 454170). 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 BLM 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.
Mendelics	RCV004701601	SCV000838953	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Ambry Genetics	RCV001019197	SCV001180525	likely benign	Hereditary cancer-predisposing syndrome	2024-01-29	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800731	SCV002046824	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in at least one individual with breast cancer (PMIDs: 33606809 (2021) and 35264596 (2022)). The frequency of this variant in the general population, 0.00014 (5/35414 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV001800731	SCV003840360	uncertain significance	not provided	2024-10-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35264596, 33606809)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000543241	SCV005878965	uncertain significance	Bloom syndrome	2024-04-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000543241	SCV001460765	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing