ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.122A>G (p.Asp41Gly) (rs63751094)

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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) RCV000675183 SCV000106148 pathogenic Lynch syndrome 2018-12-19 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability >0.99 (1.000)
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000675183 SCV000800818 pathogenic Lynch syndrome 2018-07-13 criteria provided, single submitter clinical testing Data used in classification: Single UK family with 11 informative meiosis (1:2048) (PP1_very_strong). Same amino acid residue as Asp41His (classified by INSIGHT as pathogenic) (PM5). The variant was observed in 3 independent UK families undergoing clinical diagnostic testing. There are additional reports of this variant on InSight (11 entries) and MLH1 LOVD (10 entries) (PS4_mod). The variant is absent GNOMAD NFE (63,369 individuals) and also in the remainder of the GNOMAD populations (75,263 individuals) (PM2_mod). 2/2 UK pedigrees for which we have tumour data demonstrated MSI in the tumour of the proband. Kruger S et al. Hum Mutat. 2004;24(4):351-2 report Amsterdam positive family (proband with colon cancer at 35 (ascending); [father: metachronous colon cancers: ascending colon (44), transverse colon (52) paternal grandmother: colon cancer (40)] ) with MSI-high but no loss of expression on IHC (PS3_mod). Same amino acid residue as Asp41His (classified by INSIGHT as pathogenic) (PM5). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (and also MAPP) (PP3). Additional Information (not included in classification): mRNA studies using sample from affected patient undertaken at molecular diagnostic laboratory demonstrated frame-shifting alteration in cDNA sequence: Minigene reported in Van der klift HM, et al. Mol Genet Genomic Med. 2015;3(4):327-45, reports mixed sequence products. Prior classification as Class 5 using multifactorial analysis (Insight paper 2012). Comment: Initially it was thought that this variant exerted pathogenicity through effect on splicing. However, in silico splicing predictions and splicing assay results are mixed. It may exert effect through missense impact on protein. Regardless of mechanisms, there are (i) multiple lines of generic functional evidence supporting this variant resulting in MMR deficiency and (ii) extremely strong genetic epidemiological evidence supporting pathogenicity (which is likewise agnostic to mechanism).
Invitae RCV001216631 SCV001388436 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 41 of the MLH1 protein (p.Asp41Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 15365996, 15300854, 29360550, 20233461, 15849733, 28874130). ClinVar contains an entry for this variant (Variation ID: 89684). This variant has been reported to affect MLH1 protein function (PMID: 23403630, 15475387). This variant disrupts the p.Asp41 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19419416, 12624141, 25060679, 25477341, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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