Submissions for variant NM_000249.4(MLH1):c.884G>A (p.Ser295Asn)

dbSNP: rs63750144

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075908	SCV000106925	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant allele results in splicing abberation leading to premature stop codon: full inactivation of variant allele
Ambry Genetics	RCV000215143	SCV000277766	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-10	criteria provided, single submitter	clinical testing	The c.884G>A pathogenic mutation (also known as p.S295N), located in coding exon 10 of the MLH1 gene, results from a G to A substitution at nucleotide position 884. This alteration changes the serine at codon 295 to asparagine, an amino acid with highly similar properties. This mutation was identified in an Australian woman diagnosed with MSI-H colorectal cancer at age 35 and a separate colorectal primary tumor at age 41. Both tumors showed absent MLH1 staining on IHC (Ward R et al. J. Cancer Res. Clin. Oncol. 2002 Aug;128(8):403-11). This mutation alters the highly-conserved last base pair of coding exon 10, is predicted to significantly weaken the native splice donor site by multiple in silico splicing models, and has been shown to cause exon skipping in vitro (Thompson BA et al. Hum. Mutat. 2013 Jan;34(1):200-9). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat. Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Invitae	RCV001220885	SCV001392898	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-03-29	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22949379, 26761715). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). ClinVar contains an entry for this variant (Variation ID: 90415). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 12200596). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 295 of the MLH1 protein (p.Ser295Asn). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product.
Myriad Genetics, Inc.	RCV003452784	SCV004185550	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].