ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.479C>T (p.Ala160Val) (rs63749924)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130760 SCV000185651 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-13 criteria provided, single submitter clinical testing The p.A160V variant (also known as c.479C>T), located in coding exon 6 of the MLH1 gene, results from a C to T substitution at nucleotide position 479. The alanine at codon 160 is replaced by valine, an amino acid with similar properties. In one functional study, dominant mutator effect was positive for this variant in three separate yeast-based assays. In addition, in vitro mismatch repair activity was observed to be 80.9% and MLH1 expression was observed to be >75% compared to wild type (Takahashi M et al. Cancer Res. 2007;67(10):4595-604). Based in part on these observations, this alteration has been classified as uncertain by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at []). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000524302 SCV000252650 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000522486 SCV000616780 uncertain significance not specified 2017-07-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.479C>T at the cDNA level, p.Ala160Val (A160V) at the protein level,and results in the change of an Alanine to a Valine (GCC>GTC). This variant was observed in at least one individualwith a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). One in vitro functionalstudy showed mismatch repair activity and protein expression comparable to wild-type (Takahashi 2007). MLH1Ala160Val was observed at an allele frequency of 0.103% (17/16500) in individuals of South Asian ancestry in largepopulation cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). SinceAlanine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ala160Valoccurs at a position that is not conserved and is located within the N-terminal ATPase domain (Andersen 2012). TheInternational Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertainbased on insufficient evidence for classification (Thompson 2014). In silico analyses are inconsistent regarding theeffect this variant may have on protein structure and function. Based on currently available evidence, it is unclearwhether MLH1 Ala160Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance
GeneKor MSA RCV000130760 SCV000822024 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130760 SCV000911261 likely benign Hereditary cancer-predisposing syndrome 2016-11-10 criteria provided, single submitter clinical testing

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