Submissions for variant NM_000249.4(MLH1):c.2042C>T (p.Ala681Val)

dbSNP: rs63750864

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213632	SCV000279085	likely pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21615986, 25111426, 23760103, 24710284, 12799449, 22753075, 20533529, 8993979, 31054147)
Invitae	RCV000698693	SCV000827373	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala681 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18033691, 8880570, 10037723, 12810663). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. This variant has been observed in individual(s) with suspected Lynch syndrome (PMID: 21615986, 24710284, Invitae). ClinVar contains an entry for this variant (Variation ID: 90011). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 681 of the MLH1 protein (p.Ala681Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine.
Fulgent Genetics, Fulgent Genetics	RCV000764497	SCV000895568	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415533	SCV002719809	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-17	criteria provided, single submitter	clinical testing	The p.A681V variant (also known as c.2042C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2042. The alanine at codon 681 is replaced by valine, an amino acid with similar properties. This alteration has been reported in multiple families meeting Amsterdam or Bethesda criteria (Wei W et al. BMB Rep. 2011 May; 44(5):317-22; Tian W et al. Int J Cancer, 2019 09;145:1290-1298). This alteration has also been identified as either somatic or in the germline of individuals whose colorectal tumors demonstrated loss of both MLH1 and PMS2 on immunohistochemistry and/or high microsatellite instability (Herfarth KK et al. Genes Chromosomes Cancer. 1997 Jan;18:42-9; Geurts-Giele WR et al. J. Pathol. 2014 Dec;234:548-59); Liu Y et al. PLoS ONE. 2014 Apr;9:e94170; Ambry internal data). Further, a well-characterized mutation at the same codon, p.A681T (c.2041G>A), has been identified in multiple families either meeting Amsterdam II criteria or whose family history was suggestive of HNPCC/Lynch syndrome and has also been shown to co-segregate with disease (Froggatt et al. J Med Genet. 1996 Sep; 33(9): 762-30; Shimodaira et al. Nat Genet 1998 Aug; 19(4): 384-9; Kurzawski G et al. Clin. Genet. 2006 Jan; 69(1):40-7; Barnetson RA et al. Hum. Mutat. 2008 Mar; 29(3):367-74). Based on an internal structural assessment, the p.A681V alteration locally destabilizes the folding of the MLH1 C-terminal domain (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.