ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.644A>G (p.Asn215Ser)

gnomAD frequency: 0.00003  dbSNP: rs267607775
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000627731 SCV000259718 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508449 SCV000601406 uncertain significance not specified 2017-07-06 criteria provided, single submitter clinical testing
Mendelics RCV000075791 SCV000838000 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000771523 SCV000904054 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-26 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 215 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported that this variant had a normal DNA damage response in an MLH1-null human cell line (PMID: 30998989). This variant has been reported in an individual from a Lynch syndrome family (PMID: 18561205) and in an individual affected with peritoneum cancer (PMID: 30093976). This variant has been identified in 8/251154 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 RCV000771523 SCV001187436 likely benign Hereditary cancer-predisposing syndrome 2021-11-19 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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