3-37025632-T-C

Variant names:

• chr3-37025632-T-C
• rs587782626
• NM_000249.4:c.1039-5T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000249.4(MLH1):​c.1039-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,122,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001875
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0400
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-37025632-T-C is Benign according to our data. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025632-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 142664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1039-5T>C		splice_region_variant, intron_variant	Intron 11 of 18	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1039-5T>C		splice_region_variant, intron_variant	Intron 11 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.0000146 AC: 2 AN: 136984 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000235

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000155

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000192 AC: 3 AN: 156140 AF XY: 0.0000340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000132 AC: 13 AN: 985304 Hom.: 0 Cov.: 21 AF XY: 0.0000182 AC XY: 9 AN XY: 493360

African (AFR) AF: 0.00 AC: 0 AN: 20162

American (AMR) AF: 0.00 AC: 0 AN: 22502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17194

East Asian (EAS) AF: 0.00 AC: 0 AN: 27388

South Asian (SAS) AF: 0.000183 AC: 7 AN: 38332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39792

Middle Eastern (MID) AF: 0.000920 AC: 3 AN: 3262

European-Non Finnish (NFE) AF: 0.00000258 AC: 2 AN: 776662

Other (OTH) AF: 0.0000250 AC: 1 AN: 40010

GnomAD4 genome AF: 0.0000146 AC: 2 AN: 136984 Hom.: 0 Cov.: 26 AF XY: 0.0000303 AC XY: 2 AN XY: 65926

African (AFR) AF: 0.00 AC: 0 AN: 36626

American (AMR) AF: 0.00 AC: 0 AN: 13110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3326

East Asian (EAS) AF: 0.00 AC: 0 AN: 4596

South Asian (SAS) AF: 0.000235 AC: 1 AN: 4260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000155 AC: 1 AN: 64358

Other (OTH) AF: 0.00 AC: 0 AN: 1824

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Nov 11, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2020

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. -

Oct 26, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:2

Nov 27, 2024

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]. -

Oct 18, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: BS1, BP4 -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2 Benign:1

Jun 06, 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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Oct 31, 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	-0.78
CADD	Benign	4.3
DANN	Benign	0.81
PhyloP100		-0.040
PromoterAI		0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.030		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: rs587782626; hg19: chr3-37067123;