Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM2BP6_Very_StrongBP7
The NM_000249.4(MLH1):c.1515T>C(p.Ser505Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
MLH1 Gene-Disease associations (from GenCC):
Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
Our verdict: Benign. The variant received -7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 3-37028889-T-C is Benign according to our data. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028889-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 413362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.723 with no splicing effect.
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. -
Colorectal cancer, hereditary nonpolyposis, type 2Benign:1
Nov 22, 2024
Myriad Genetics, Inc.
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Lynch syndromeBenign:1
Dec 01, 2023
All of Us Research Program, National Institutes of Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Muir-Torré syndromeBenign:1
Nov 18, 2024
Department of Pathology and Laboratory Medicine, Sinai Health System