ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2135G>T (p.Trp712Leu)

gnomAD frequency: 0.00001  dbSNP: rs63750561
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003153597 SCV000543663 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 712 of the MLH1 protein (p.Trp712Leu). This variant is present in population databases (rs63750561, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 29263802, 35449176). ClinVar contains an entry for this variant (Variation ID: 405437). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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.
Color Diagnostics, LLC DBA Color Health RCV001180389 SCV001345312 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV001180389 SCV002729058 likely benign Hereditary cancer-predisposing syndrome 2022-08-17 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.

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