chr3-37025629-T-TTA

Position:

• chr3-37025629-T-TTA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000249.4(MLH1):​c.1039-8_1039-7insTA variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0980

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 3-37025629-T-TTA is Benign according to our data. Variant chr3-37025629-T-TTA is described in ClinVar as [Likely_benign]. Clinvar id is 182538.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 = 0.000614 (83/135224) while in subpopulation AFR AF= 0.00194 (66/33956). AF 95% confidence interval is 0.00157. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1039-8_1039-7insTA		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1039-8_1039-7insTA		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000249.4	ENSP00000231790	P1

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

GnomAD3 exomes AF: 0.000247 AC: 29 AN: 117468 Hom.: 0 AF XY: 0.000207 AC XY: 14 AN XY: 67558

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 SAS exome AF: 0.000365

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

Gnomad4 AFR exome AF: 0.00370

Gnomad4 AMR exome AF: 0.000577

Gnomad4 ASJ exome AF: 0.000401

Gnomad4 EAS exome AF: 0.000414

Gnomad4 SAS exome AF: 0.000549

Gnomad4 FIN exome AF: 0.000518

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00111

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

Gnomad4 AFR AF: 0.00194

Gnomad4 AMR AF: 0.0000728

Gnomad4 ASJ AF: 0.00151

Gnomad4 EAS AF: 0.000203

Gnomad4 SAS AF: 0.000224

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000110

Gnomad4 OTH AF: 0.00110

Alfa AF: 0.000733 Hom.: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 11, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2014	The variant is found in HEREDICANCER,BR-OV-HEREDIC panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	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 provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

MLH1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Breast carcinoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs535965616; hg19: chr3-37067120;