chr3-37028889-T-C

Variant names:

• chr3-37028889-T-C
• rs774699212
• NM_000249.4:c.1515T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM2 BP6_Very_Strong BP7

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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MLH1 NM_000249.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.723
• Publications: 0 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1515T>C	p.Ser505Ser	synonymous_variant	Exon 13 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1515T>C	p.Ser505Ser	synonymous_variant	Exon 13 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251472 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 0.000101 AC: 4 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Feb 17, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2015

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. -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign: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 syndrome Benign: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 syndrome Benign:1

Nov 18, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 31, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.2
DANN	Benign	0.57
PhyloP100		-0.72

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: rs774699212; hg19: chr3-37070380;