ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.317G>A (p.Ser106Asn) (rs368208495)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000582409 SCV000689878 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589043 SCV000696160 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.317G>A (p.Ser106Asn) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121396 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000813260 SCV000953612 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 106 of the MLH1 protein (p.Ser106Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs368208495, ExAC 0.01%). This variant has been reported in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 491706). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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