Submissions for variant NM_000249.4(MLH1):c.2161T>C (p.Tyr721His)

gnomAD frequency: 0.00001  dbSNP: rs1453792999

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781533	SCV000919639	uncertain significance	not specified	2018-02-16	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2161T>C (p.Tyr721His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245906 control chromosomes (in gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2161T>C has not been reported in the literature in individuals affected with Lynch Syndrome, but it was found in a individual without a personal or family history of colon cancer or other Lynch syndrome-associated cancers (Pritchard 2012). These report(s) does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000793117	SCV000932457	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 721 of the MLH1 protein (p.Tyr721His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 633306). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV001188243	SCV001355264	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 721 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Sema4, Sema4	RCV001188243	SCV002528723	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-07	criteria provided, single submitter	curation
Ambry Genetics	RCV001188243	SCV002731308	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	clinical testing	The p.Y721H variant (also known as c.2161T>C), located in coding exon 19 of the MLH1 gene, results from a T to C substitution at nucleotide position 2161. The tyrosine at codon 721 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004001533	SCV004843289	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 721 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.