Submissions for variant NM_000249.4(MLH1):c.1270G>A (p.Ala424Thr)

gnomAD frequency: 0.00004  dbSNP: rs377433038

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206553	SCV000260574	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657001	SCV000566030	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	In silico analysis indicates 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: 25111426, Plazzer2024[preprint], 35534704, 22753075)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485106	SCV000601350	uncertain significance	not specified	2017-03-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562644	SCV000662024	likely benign	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000562644	SCV000903017	likely benign	Hereditary cancer-predisposing syndrome	2015-12-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000987172	SCV001136405	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000987172	SCV004190640	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-12-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000657001	SCV004226066	uncertain significance	not provided	2022-02-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997623	SCV004840986	likely benign	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000485106	SCV005203947	uncertain significance	not specified	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1270G>A (p.Ala424Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 1613940 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Lynch Syndrome (5.5e-05 vs 0.00071), allowing no conclusion about variant significance. c.1270G>A has been reported in the literature in individuals with a family history of cancer (deOliveira_2022) and inflammatory bowel disease-associated colorectal cancers (Din_2018). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 29950348, 35534704). ClinVar contains an entry for this variant (Variation ID: 220203). Based on the evidence outlined above, the variant was classified as uncertain significance.