3-37025608-A-ATTTTTT

Position:

• chr3-37025608-A-ATTTTTT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000249.4(MLH1):​c.1039-13_1039-8dupTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0340

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 3-37025608-A-ATTTTTT is Benign according to our data. Variant chr3-37025608-A-ATTTTTT is described in ClinVar as [Benign]. Clinvar id is 413363.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37025608-A-ATTTTTT is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1039-13_1039-8dupTTTTTT		splice_region_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.1039-13_1039-8dupTTTTTT		splice_region_variant, intron_variant		1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.0000414 AC: 2 AN: 48288 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000307

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000464 AC: 12 AN: 258456 Hom.: 0 Cov.: 0 AF XY: 0.0000390 AC XY: 5 AN XY: 128310

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000258

Gnomad4 OTH exome AF: 0.000115

GnomAD4 genome AF: 0.0000414 AC: 2 AN: 48276 Hom.: 0 Cov.: 0 AF XY: 0.0000465 AC XY: 1 AN XY: 21494

Gnomad4 AFR AF: 0.0000831

Gnomad4 AMR AF: 0.000307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
La Branchor		0.24
BranchPoint Hunter		2.0

Splicing

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;