3-37025608-ATTTTTTTTT-ATTTTTTT

Position:

• chr3-37025608-ATTTTTTTTT-ATTTTTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000249.4(MLH1):​c.1039-9_1039-8del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 305,654 control chromosomes in the GnomAD database, including 31 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0077 (31 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.431

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 -16 ACMG points.

• BP6: Variant 3-37025608-ATT-A is Benign according to our data. Variant chr3-37025608-ATT-A is described in ClinVar as [Likely_benign]. Clinvar id is 433863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00767 (1974/257382) while in subpopulation AMR AF= 0.0142 (18/1268). AF 95% confidence interval is 0.0108. There are 31 homozygotes in gnomad4_exome. There are 956 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1039-9_1039-8del		intron_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1039-9_1039-8del		intron_variant		1	NM_000249.4	ENSP00000231790	P1

Frequencies

GnomAD3 genomes AF: 0.000166 AC: 8 AN: 48284 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000481

Gnomad SAS AF: 0.000745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000115

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00810 AC: 113 AN: 13956 Hom.: 3 AF XY: 0.00536 AC XY: 45 AN XY: 8400

Gnomad AFR exome AF: 0.0746

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.0556

Gnomad SAS exome AF: 0.00830

Gnomad FIN exome AF: 0.00299

Gnomad NFE exome AF: 0.00801

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00767 AC: 1974 AN: 257382 Hom.: 31 AF XY: 0.00748 AC XY: 956 AN XY: 127796

Gnomad4 AFR exome AF: 0.00839

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.00479

Gnomad4 EAS exome AF: 0.00564

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.00745

Gnomad4 OTH exome AF: 0.00851

GnomAD4 genome AF: 0.000166 AC: 8 AN: 48272 Hom.: 0 Cov.: 0 AF XY: 0.000233 AC XY: 5 AN XY: 21492

Gnomad4 AFR AF: 0.000249

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000484

Gnomad4 SAS AF: 0.000749

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000115

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	Mar 21, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
La Branchor		0.24
BranchPoint Hunter		2.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs57509953; hg19: chr3-37067099;