Submissions for variant NM_000249.4(MLH1):c.1721T>C (p.Leu574Pro)

dbSNP: rs63751608

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075320	SCV000106314	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Abrogated function & co-segregation with disease
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698457	SCV000827122	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2018-12-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect MLH1 protein function (PMID: 21404117, 23403630, 9697702, 17510385, 10037723, 15864295, 12810663, 18094436, 11427529). This variant has been observed in several individuals affected with Lynch syndrome-related cancers (PMID: 7757073, 15365995), and was shown to segregate with colon cancer in a family (PMID: 7757073). ClinVar contains an entry for this variant (Variation ID: 89846). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 574 of the MLH1 protein (p.Leu574Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075320	SCV000887320	likely pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.1721T>C has a 95.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV002408575	SCV002716642	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	clinical testing	The p.L574P variant (also known as c.1721T>C), located in coding exon 15 of the MLH1 gene, results from a T to C substitution at nucleotide position 1721. The leucine at codon 574 is replaced by proline, an amino acid with similar properties. This alteration was identified as somatic in an individual with a second pathogenic somatic alteration and whose Lynch-related tumor demonstrated high microsatellite instability and loss of MLH1 and PMS2 expression on immunohistochemistry with negative MLH1 promoter hypermethylation (Ambry internal data). This alteration co-segregates with disease in a Korean family that meets Amsterdam criteria (Han HJ et al. Hum Mol Genet, 1995 Feb;4:237-42) and was also identified in a 32-year-old Korean male with colorectal cancer from a cohort of 141 HNPCC families (Shin YK et al. Hum Mutat, 2004 Oct;24:351). Functional studies demonstrate reduced MMR activity relative to wild-type MLH1, a dominant negative mutator effect in yeast, aberrant interaction with PMS2 that is similar to pathogenic controls, and reduced MLH1 protein stability/expression (Shimodaira H et al. Nat Genet, 1998 Aug;19:384-9; Guerrette S et al. J Biol Chem, 1999 Mar;274:6336-41; Kondo E et al. Cancer Res, 2003 Jun;63:3302-8; Takahashi M et al. Cancer Res, 2007 May;67:4595-604; Fan Y et al. Clin Cancer Res, 2007 Dec;13:7515-21; Hardt K et al. Fam Cancer, 2011 Jun;10:273-84; Hinrichsen I et al. Clin Cancer Res, 2013 May;19:2432-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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.