ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.302G>A (p.Gly101Asp) (rs267607727)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075624 SCV000106626 likely pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.968
GeneDx RCV000481030 SCV000565141 likely pathogenic not provided 2021-02-02 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: reduced protein expression and MMR repair activity compared to wild type (Ellison 2004, Hinrichsen 2013); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and/or family histories consistent with Lynch syndrome (Taylor 2003, Tournier 2008); This variant is associated with the following publications: (PMID: 19224586, 15475387, 23403630, 22290698, 25525159, 14635101, 18561205, 31784484)
Ambry Genetics RCV000568721 SCV000676037 likely pathogenic Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing The p.G101D variant (also known as c.302G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 302. The glycine at codon 101 is replaced by aspartic acid, an amino acid with similar properties. Two in vitro functional studies demonstrated reduced MMR function for p.G101D when compared to wild-type MLH1 in yeast (Ellison AR et al., Nucleic Acids Res. 2004 ; 32(18):5321-38; Hinrichsen I et al., Clin. Cancer Res. 2013 May; 19(9):2432-41). The Hinrichsen study also found decreased expression (10-20% relative expression) for this variant when compared to wild-type. Based on internal structural analysis, this variant is highly destabilizing and resides in a known motif within close proximity to known pathogenic variants (Wu H et al., Acta Crystallogr F Struct Biol Commun 2015 Aug; 71(Pt 8):981-5; Hol WG et al., Nature 1978 Jun; 273(5662):443-6). This variant was also identified in a family meeting Bethesda guidelines (Taylor CF et al., Hum. Mutat. 2003 Dec; 22(6):428-33). This amino acid position is highly conserved in available vertebrate species. This variant is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao E et al., Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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