chr3-37028774-T-G

Variant names:

• chr3-37028774-T-G
• rs372053184
• NM_000249.4:c.1410-10T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000249.4(MLH1):​c.1410-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Scores: Splicing: ADA: 0.0004189
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.07
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 3-37028774-T-G is Benign according to our data. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37028774-T-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00044 (67/152338) while in subpopulation AFR AF = 0.00147 (61/41584). AF 95% confidence interval is 0.00117. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1410-10T>G		intron_variant	Intron 12 of 18	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1410-10T>G		intron_variant	Intron 12 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251424 AF XY: 0.0000515

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34 AN XY: 727234

African (AFR) AF: 0.00114 AC: 38 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111980

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74494

African (AFR) AF: 0.00147 AC: 61 AN: 41584

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000397 Hom.: 0

Bravo AF: 0.000404

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Oct 16, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 27, 2024

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2+BP4+BP6+BP7 -

not specified Benign:2

Apr 06, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MLH1 c.1410-10T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.4e-05 in 251424 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.13 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1410-10T>G has been reported in the literature as a VUS in individuals with colorectal cancer (example, Poynter_2008, Guindalini_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Feb 27, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Muir-Torré syndrome Benign:2

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Jun 29, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.70
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.10
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: rs372053184; hg19: chr3-37070265;