Submissions for variant NM_000249.4(MLH1):c.1984A>C (p.Thr662Pro)

dbSNP: rs587778964

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075450	SCV000106447	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Abrogated function (2 independent assays with reduced expression) & 6 MSI-H tumours
Invitae	RCV000524263	SCV000260401	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 662 of the MLH1 protein (p.Thr662Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 11726306, 11754112, 16341550, 19621678, 21404117). ClinVar contains an entry for this variant (Variation ID: 89968). 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 not expected to disrupt MLH1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17510385, 20533529, 23403630, 31332305). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780422	SCV000917665	uncertain significance	not specified	2018-12-11	criteria provided, single submitter	clinical testing	Variant summary: The variant, MLH1 c.1984A>C (p.Thr662Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In vitro/vivo studies have shown that this variant results in a partial deletion of exon 17, reduces interaction with PMS2, and significantly reduces protein expression (Pagenstecher_2006, Kosinski_2010, Hinrichsen_2013). The variant, when expressed from cDNA, has been shown not to have a significant reduction in MMR activity by multiple studies, however, the MMR proficiency of the partial deletion of exon 17 caused by the variant was not addressed (Takahashi_2007, Hinrichsen_2013). The variant was absent in 276836 control chromosomes (gnomAD and publications) and has been reported in the literature in individuals affected with Lynch Syndrome (Hardt_2011, Pagenstecher_2006, Kruger_2001, Takahashi_2007). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS possibly pathogenic.
Ambry Genetics	RCV001013906	SCV001174548	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-10-01	criteria provided, single submitter	clinical testing	The p.T662P variant (also known as c.1984A>C), located in coding exon 17 of the MLH1 gene, results from an A to C substitution at nucleotide position 1984. The threonine at codon 662 is replaced by proline, an amino acid with highly similar properties. This variant was reported in four individuals from four different families who met Bethesda guidelines. Furthermore, tumor analysis revealed MSI-H in all four individuals and IHC revealed three individuals had loss of MLH1 as well as PMS2 and one individual had loss of MLH1 (Hardt K et al., Fam. Cancer 2011 Jun; 10(2):273-84). This variant has also been reported in families meeting Amsterdam criteria (Müller-Koch Y et al. Eur. J. Med. Res., 2001 Nov;6:473-82; Krüger S et al. Hum. Mutat., 2002 Jan;19:82). Additional studies combining family history, segregation with disease, functional analyses, and/or in silico predictions have also demonstrated that this alteration is likely pathogenic (Thompson BA et al., Nat. Genet. 2014 Feb; 46(2):107-15). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003451089	SCV004188221	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003451089	SCV004195035	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-24	criteria provided, single submitter	clinical testing