rs535965616

Variant names:

• chr3-37025629-T-TTA
• rs535965616
• NM_000249.4:c.1039-8_1039-7insTA

Your query was ambiguous. Multiple possible variants found:

• chr3-37025629-T-TTA
• chr3-37025629-T-TTAA
• chr3-37025629-T-TTAAAA
• chr3-37025629-T-TTTA
• chr3-37025629-T-TTTTA
• chr3-37025629-T-TTTTTA
• chr3-37025629-T-TTTTTAA
• chr3-37025629-T-TTTTTAAAA
• chr3-37025629-T-TTTTTTA
• chr3-37025629-T-TTTTTTTA
• chr3-37025629-T-TTTTTTTTA
• chr3-37025629-T-TTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTTTTTTTTTA
• chr3-37025629-T-TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000249.4(MLH1):​c.1039-8_1039-7insTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.0980
• Publications: 3 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 -8 ACMG points.

• BP6: Variant 3-37025629-T-TTA is Benign according to our data. Variant chr3-37025629-T-TTA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 182538.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.1039-8_1039-7insTA		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.1039-8_1039-7insTA		splice_region_variant, intron_variant	Intron 11 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.000614 AC: 83 AN: 135234 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000729

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.000223

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000110

Gnomad OTH AF: 0.00110

GnomAD2 exomes AF: 0.000247 AC: 29 AN: 117468 AF XY: 0.000207

Gnomad AFR exome AF: 0.000342

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000202

Gnomad NFE exome AF: 0.000259

Gnomad OTH exome AF: 0.000441

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00115 AC: 1257 AN: 1090526 Hom.: 0 Cov.: 20 AF XY: 0.00118 AC XY: 636 AN XY: 538840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00370 AC: 76 AN: 20528

American (AMR) AF: 0.000577 AC: 10 AN: 17334

Ashkenazi Jewish (ASJ) AF: 0.000401 AC: 7 AN: 17458

East Asian (EAS) AF: 0.000414 AC: 12 AN: 28964

South Asian (SAS) AF: 0.000549 AC: 21 AN: 38246

European-Finnish (FIN) AF: 0.000518 AC: 19 AN: 36672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3178

European-Non Finnish (NFE) AF: 0.00120 AC: 1064 AN: 884828

Other (OTH) AF: 0.00111 AC: 48 AN: 43318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000614 AC: 83 AN: 135224 Hom.: 0 Cov.: 19 AF XY: 0.000566 AC XY: 37 AN XY: 65412

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00194 AC: 66 AN: 33956

American (AMR) AF: 0.0000728 AC: 1 AN: 13732

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 5 AN: 3318

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4930

South Asian (SAS) AF: 0.000224 AC: 1 AN: 4464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.000110 AC: 7 AN: 63888

Other (OTH) AF: 0.00110 AC: 2 AN: 1826

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000733 Hom.: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4

Feb 11, 2022

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 07, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in HEREDICANCER,BR-OV-HEREDIC panel(s). -

Sep 03, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Jun 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MLH1-related disorder Benign:1

Apr 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast carcinoma Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.098
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs535965616; hg19: chr3-37067120;