ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1667G>A (p.Ser556Asn) (rs63751596)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520479 SCV000618169 likely pathogenic not provided 2017-03-07 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1677G>A at the cDNA level. Located in the last nucleotide of exon 14, this variant is predicted to disrupt the natural splice donor site and causes abnormal splicing. This variant has been identified in an individual with colon cancer in a family meeting Amsterdam criteria (Sjursen 2016). Another nucleotide substitution at this position, MLH1 c.1677G>T, has been identified in a family meeting Amsterdam criteria and a splicing assay showed that this variant result in abnormal splicing (Sharp 2004). Although the nucleotide substitution results in the change of a Serine to an Asparagine at codon 556, we are using only the nucleotide nomenclature to refer to the variant since the defect is likely to be one of splicing rather than a resulting missense variant. MLH1 c.1677G>A was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). The nucleotide which is altered, a guanine (G) at base 1677, is conserved across species. Based on the current evidence, we consider this variant to be likely pathogenic.
Ambry Genetics RCV001012628 SCV001173105 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-12 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Last nucleotide of exon;Other data supporting pathogenic classification;Well-characterized mutation at same position
Invitae RCV001046224 SCV001210118 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 556 of the MLH1 protein (p.Ser556Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 14 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome, and has been observed to segregate with colorectal cancer in a family (PMID: 28135145, 27064304, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 449776). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093684 SCV001250865 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249931 SCV001423873 likely pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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