Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000128924 | SCV000172794 | likely benign | Hereditary cancer-predisposing syndrome | 2018-10-29 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
Gene |
RCV000034544 | SCV000211118 | likely benign | not provided | 2019-09-11 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 17510385, 22703879, 8938136, 17348456, 10970186, 18383312, 16341804, 11376800, 25637381, 27600092, 31159747, 31332305) |
Invitae | RCV001085205 | SCV000284039 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-28 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000662533 | SCV000785103 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2017-04-18 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000128924 | SCV000822021 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000128924 | SCV000910738 | likely benign | Hereditary cancer-predisposing syndrome | 2015-07-20 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781539 | SCV000919656 | likely benign | not specified | 2023-12-11 | criteria provided, single submitter | clinical testing | Variant summary: MLH1 c.1964T>C (p.Ile655Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251246 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.6e-05 vs 0.00071), allowing no conclusion about variant significance. c.1964T>C has been reported in the literature in individuals with a personal or family history of colorectal or other MLH1-related cancers, and at-least one instance of co-occurrence in a patient with hMLH1 promoter hypermethylation suggestive of a sporadic etiology has been ascertained (e.g., Irmejs_2007, Keller_1996, Potocnik_2001, Ravnik-Glavac_2000, Schubert_2019, Svensson_2022, Tsoaousis_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch syndrome. A co-occurrence with another pathogenic variant has been reported (MSH2 c.1786_1788del, p.Asn596del; Irmejs_2007), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 74% of normal activity in an in-vitro MMR assay and >75% relative MLH1 expression (Takahashi_2007). The following publications have been ascertained in the context of this evaluation (PMID: 31697235, 22290698, 25637381, 18383312, 11179758, 17348456, 22703879, 8938136, 27647783, 11376800, 10970186, 30426508, 35430768, 17510385, 31159747). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign, n = 6; VUS, n = 6). Based on the evidence outlined above, the variant was classified as likely benign. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000034544 | SCV001470332 | uncertain significance | not provided | 2019-12-29 | criteria provided, single submitter | clinical testing | |
Institute for Clinical Genetics, |
RCV000034544 | SCV002009369 | likely benign | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000781539 | SCV002070339 | uncertain significance | not specified | 2020-08-03 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.1964T>C, in exon 17 that results in an amino acid change, p.Ile655Thr. This sequence change has been described in the gnomAD database with a low frequency of 0.016% in the European sub-population (dbSNP rs63751225). The p.Ile655Thr change affects a poorly conserved amino acid residue located in a domain of the MLH1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile655Thr substitution. The p.Ile655Thr change has previously been described in a family with gastric cancer (PMID: 8938136); however, functional studies have demonstrated mismatch repair activity similar to that of the wild type allele in the presence of this sequence change (PMID: 17510385). Due to these contrasting evidences, the clinical significance of the p.Ile655Thr change remains unknown at this time. |
Center for Genomic Medicine, |
RCV000781539 | SCV002550465 | uncertain significance | not specified | 2024-02-06 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000034544 | SCV003916425 | uncertain significance | not provided | 2023-06-01 | criteria provided, single submitter | clinical testing | MLH1: PM2, PP4:Moderate |
Myriad Genetics, |
RCV000662533 | SCV004018170 | likely benign | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-03-15 | criteria provided, single submitter | clinical testing | This variant is considered likely benign. 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]. |
Prevention |
RCV003944879 | SCV004773342 | likely benign | MLH1-related condition | 2020-03-03 | criteria provided, single submitter | clinical testing | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). |
Biesecker Lab/Clinical Genomics Section, |
RCV000034544 | SCV000043329 | variant of unknown significance | not provided | 2012-07-13 | no assertion criteria provided | research | Converted during submission to Uncertain significance. |
CSER _CC_NCGL, |
RCV000148623 | SCV000190338 | uncertain significance | Colorectal cancer, non-polyposis | 2014-06-01 | no assertion criteria provided | research |