Submissions for variant NM_000249.4(MLH1):c.1855G>C (p.Ala619Pro)

dbSNP: rs267607866

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075387	SCV000106383	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics	RCV000165622	SCV000216358	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-04-26	criteria provided, single submitter	clinical testing	The p.A619P variant (also known as c.1855G>C), located in coding exon 16 of the MLH1 gene, results from a G to C substitution at nucleotide position 1855. The alanine at codon 619 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in one German family meeting Amsterdam II criteria; the index case was diagnosed with MSI-H colorectal cancer at age 41 (Hardt K, Fam. Cancer 2011 Jun; 10(2):273-84). The A619 residue is located in a structured region with known function, and internal structural analysis indicates that a proline substitution is expected to result in a significant decrease in structural stability (Ambry internal data; Dombrovsky L et al. http://www.rcsb.org/pdb/explore/explore.do?structureId=3RBN). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be benign <span style="background-color:initial">by PolyPhen <span style="background-color:initial">but deleterious by SIFT in silico<span style="background-color:initial"> analyses. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000548274	SCV000625103	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 619 of the MLH1 protein (p.Ala619Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 10612827, 18561205, 21404117, 21520333, 23729658, 28514183). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89909). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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.
Myriad Genetics, Inc.	RCV003451073	SCV004188432	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-24	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 30504929, 31784484]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18561205, 21404117].