Submissions for variant NM_000249.4(MLH1):c.1457C>T (p.Ser486Phe)

dbSNP: rs532873141

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000460169	SCV000543599	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 486 of the MLH1 protein (p.Ser486Phe). This variant is present in population databases (rs532873141, gnomAD 0.006%). 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: 405411). 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.
GeneDx	RCV000481335	SCV000566435	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least one individual with breast cancer, as well as in unaffected controls in a study of DNA mismatch repair (MMR) genes (Penkert et al., 2018; Zhang et al., 2022); This variant is associated with the following publications: (PMID: 22753075, 30086788, 34172528)
Ambry Genetics	RCV000574118	SCV000673832	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-29	criteria provided, single submitter	clinical testing	The p.S486F variant (also known as c.1457C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1457. The serine at codon 486 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in a breast cancer patient (Penkert J et al. Breast Cancer Res, 2018 Aug;20:87). This alteration was also reported in two carriers from a study of a cohort representative of the Chinese general population (Zhang L et al. J Med Genet, 2022 Jul;59:652-661). This amino acid position is 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	RCV000574118	SCV000684745	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 486 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 30086788). This variant has also been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	RCV000574118	SCV002528651	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-02	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153588	SCV003843558	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000656	SCV004841014	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 486 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 30086788). This variant has also been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.