Submissions for variant NM_000249.4(MLH1):c.887T>C (p.Leu296Ser)

gnomAD frequency: 0.00001  dbSNP: rs63750547

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222772	SCV000276858	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	The p.L296S variant (also known as c.887T>C), located in coding exon 11 of the MLH1 gene, results from a T to C substitution at nucleotide position 887. The leucine at codon 296 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in a patient with a personal history of invasive breast cancer before age 40 (Rummel SK et al. Breast Cancer Res. Treat., 2017 Aug;164:593-601). This amino acid position is highly 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.
GeneDx	RCV000588023	SCV000616782	uncertain significance	not provided	2023-09-20	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 individuals with a personal and/or family history of MLH1-related cancers and other cancers in published literature (Rummel et al., 2017; Cho et al., 2018; Li et al., 2020); This variant is associated with the following publications: (PMID: 28503720, 30089731, 31391288, 22753075)
Invitae	RCV000527338	SCV000625205	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-06-27	criteria provided, single submitter	clinical testing	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 232668). This missense change has been observed in individual(s) with breast cancer, basal cell carcinoma (PMID: 28503720, 30089731). This variant is present in population databases (rs63750547, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 296 of the MLH1 protein (p.Leu296Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824695	SCV000696188	uncertain significance	not specified	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.887T>C (p.Leu296Ser) results in a non-conservative amino acid change located in the S5 domain 2-like fold (IPR013507) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant is located close to a splice-site, therefore might also affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.6e-06 in 775556 control chromosomes (gnomAD v4.0). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.887T>C has been reported in the literature in individuals affected with various tumor phenotypes, including tumor(s) that belong to the Lynch syndrome (LS) tumor spectrum (e.g. Li_2020), and also other tumors that are not part of the LS tumor spectrum (e.g. Cho_2018, Rummel_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 232668). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000663054	SCV000786104	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-02-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222772	SCV000905470	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 296 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 been reported in individuals affected with breast cancer (PMID: 28503720), basal cell carcinoma (PMIDL 30089731), and unspecified cancer suspected of Lynch syndrome (PMID: 31391288). This variant has been identified in 1/251430 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.
Myriad Genetics, Inc.	RCV000663054	SCV004020244	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered likely 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.
Baylor Genetics	RCV000663054	SCV004190611	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997993	SCV004840917	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing