Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7
The NM_000249.4(MLH1):c.990C>A(p.Ile330Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. I330I) has been classified 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: Likely_benign. The variant received -5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
Variant 3-37020415-C-A is Benign according to our data. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37020415-C-A is described in CliVar as Likely_benign. Clinvar id is 1768568.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-2.26 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. -