ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1855G>C (p.Ala619Pro) (rs267607866)

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Total submissions: 3
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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. 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 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 619 of the MLH1 protein (p.Ala619Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with suspected or reported Lynch syndrome (PMID: 21404117, 18561205, 28514183, 10612827, 21520333). It has also been observed to segregate with colon cancer in a family (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 89909). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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.

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