ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1667G>A (p.Ser556Asn) (rs63751596)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520479 SCV000618169 likely pathogenic not provided 2019-09-10 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Whitworth 2015, Sjursen 2016, Yurgelun 2017); This variant is associated with the following publications: (PMID: 25248401, 27064304, 22949387, 28135145, 30521064, 30720243)
Ambry Genetics RCV001012628 SCV001173105 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing The c.1667G>A variant (also known as p.S556N), located in coding exon 14 of the MLH1 gene, results from a G to A substitution at nucleotide position 1667. The amino acid change results in serine to asparagine at codon 556, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 14, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in multiple families fulfilling Amsterdam criteria (Sjursen W et al. Mol Genet Genomic Med. 2016 Mar;4:223-31; Yurgelun MBJ. Clin. Oncol. 2017 Apr;35(10):1086-1095). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Another alteration at this same nucleotide position, c.1667G>T, has been shown to result in the use of a cryptic splice site that leads to a frameshift and a new stop codon which predicted to create a truncated protein (Sharp et al. Hum Mutat. 2004 Sep;24(3):272; Desmet et al. Nucleic Acids Res. 2009 May;37(9):e67). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001046224 SCV001210118 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 556 of the MLH1 protein (p.Ser556Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 14 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome, and has been observed to segregate with colorectal cancer in a family (PMID: 28135145, 27064304, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 449776). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093684 SCV001250865 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249931 SCV001423873 likely pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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