Submissions for variant NM_000249.4(MLH1):c.1202G>A (p.Ser401Asn)

gnomAD frequency: 0.00001  dbSNP: rs587779951

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115454	SCV000149363	uncertain significance	not provided	2021-08-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145)
Ambry Genetics	RCV000222306	SCV000275412	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	The p.S401N variant (also known as c.1202G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1202. The serine at codon 401 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000222306	SCV000684728	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 401 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 been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 1/251370 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.
Counsyl	RCV000663036	SCV000786074	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV000813295	SCV000953651	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-07	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 401 of the MLH1 protein (p.Ser401Asn). This variant is present in population databases (rs587779951, gnomAD 0.0009%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145, 30877237). ClinVar contains an entry for this variant (Variation ID: 127611). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824610	SCV002074418	uncertain significance	not specified	2022-01-24	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1202G>A (p.Ser401Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251370 control chromosomes (gnomAD). c.1202G>A has been reported in the literature in individuals affected with colorectal cancers, including those suspected with Lynch Syndrome (Yurgelun_2017, Pearlman_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Myriad Genetics, Inc.	RCV000663036	SCV004018151	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000663036	SCV004190663	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997260	SCV004840972	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 401 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 been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 1/251370 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.