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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524263	SCV000260401	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-24	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, 34897210). ClinVar contains an entry for this variant (Variation ID: 89968). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive 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	RCV005237503	SCV000917665	likely pathogenic	Hereditary nonpolyposis colon cancer	2024-12-30	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1984A>C (p.Thr662Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249912 control chromosomes. c.1984A>C has been reported in the literature in multiple individuals affected with Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer Lynch Syndrome (example, Hardt_2011, Pagenstecher_2006, Kruger_2001, Takahashi_2007). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Takahashi_2007, Kosinski_2010, Hinrichsen_2013, Borras_2012). The most pronounced variant effect results in a moderate (approx 60%) reduction in mismatch repair (MMR) activity (Takahashi_2007) while another study reporting a proficient MMR activity characterized the variant as being stability deficient (Hinrichsen_2013). The following publications have been ascertained in the context of this evaluation (PMID: 22736432, 18383312, 21404117, 23403630, 20533529, 11754112, 17192056, 36454741, 16341550, 17510385, 24362816, 23760103). ClinVar contains an entry for this variant (Variation ID: 89968). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001013906	SCV001174548	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-22	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, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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