3-37050552-T-C

Variant names:

• chr3-37050552-T-C
• rs63749875
• NM_000249.4:c.2170T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000249.4(MLH1):​c.2170T>C​(p.Leu724Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L724L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MLH1 NM_000249.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.36
• Publications: 10 publications found

Genes affected

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
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Lynch syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-37050552-T-C is Benign according to our data. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050552-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 433873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.36 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.2170T>C	p.Leu724Leu	synonymous_variant	Exon 19 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.2170T>C	p.Leu724Leu	synonymous_variant	Exon 19 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 23, 2014

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:1

Dec 02, 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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Oct 26, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.9
DANN	Benign	0.89
PhyloP100		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs63749875; hg19: chr3-37092043;