Submissions for variant NM_000249.4(MLH1):c.962G>A (p.Ser321Asn)

dbSNP: rs63750286

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567071	SCV000669584	uncertain significance	Hereditary cancer-predisposing syndrome	2016-10-03	criteria provided, single submitter	clinical testing	The p.S321N variant (also known as c.962G>A), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 962. The serine at codon 321 is replaced by asparagine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs63750286, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003225091	SCV003921383	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075)
Invitae	RCV003758826	SCV004537686	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 321 of the MLH1 protein (p.Ser321Asn). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 483567). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs63750286, gnomAD 0.007%).
All of Us Research Program, National Institutes of Health	RCV004001028	SCV004840933	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 321 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/251378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.