ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2210A>T (p.Asp737Val) (rs267607885)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115474 SCV000149383 uncertain significance not provided 2021-03-04 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in trans with a MLH1 pathogenic variant in an individual meeting Amsterdam criteria; however, the variant was shown to not segregate with disease (Mangold 2005, Pagenstecher 2006); Published functional studies demonstrate no damaging effect: shown to be non-pathogenic via oligonucleotide-directed mutation screening (Houlleberghs 2020); This variant is associated with the following publications: (PMID: 9419403, 22949387, 18383312, 15849733, 21404117, 16341550, 23760103, 23435383, 31784484)
Invitae RCV000791373 SCV000254367 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 737 of the MLH1 protein (p.Asp737Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with colorectal cancer (PMID: 16341550). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.2210A>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 90090). 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.
Ambry Genetics RCV000563079 SCV000662010 likely benign Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color Health, Inc RCV000563079 SCV000684805 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-03 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with valine at codon 737 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a HNPCC family who also had a pathogenic splice mutation in the same gene, in which the c.2210A>T variant is stated to not segregate with disease (PMID: 15849733, 16341550, 21404117). This variant has been identified in 1/251274 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000115474 SCV001500307 uncertain significance not provided 2020-08-01 criteria provided, single submitter clinical testing

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