ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1331A>G (p.Asn444Ser)

dbSNP: rs763189331
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001088444 SCV000556001 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-10-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587089 SCV000696107 likely benign not provided 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 5/5 in silico programs predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121154, which does not exceed the predicted maximum expected allele frequency for a pathogenic MLH1 variant of 1/1407. The variant of interest has been reported in multiple affected individuals to co-occur with another known pathogenic MLH1 mutation, c.2041G>A (p.Ala681Thr) and 1 individual with c.1888_1892delATTGA (p.Ile630X). A reputable database classifies the variant as "Neutral." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as likely benign until additional information becomes available.
Color Diagnostics, LLC DBA Color Health RCV001190846 SCV001358438 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-08 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 444 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 1 individual affected with colorectal cancer (PMID: 23354017). This variant has been identified in 1/251248 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001190846 SCV002692923 likely benign Hereditary cancer-predisposing syndrome 2019-12-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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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