NM_000249.4:c.1039-13_1039-8dupTTTTTT

Variant names:

• chr3-37025608-A-ATTTTTT
• rs57509953
• NM_000249.4:c.1039-13_1039-8dupTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -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
• 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: Likely_benign. The variant received -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 VariationId is 413363.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1039-13_1039-8dupTTTTTT		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.1039-29_1039-28insTTTTTT		intron_variant	Intron 11 of 18	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

African (AFR) AF: 0.000599 AC: 2 AN: 3340

American (AMR) AF: 0.00157 AC: 2 AN: 1274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2090

East Asian (EAS) AF: 0.00 AC: 0 AN: 3044

South Asian (SAS) AF: 0.000189 AC: 1 AN: 5298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 526

European-Non Finnish (NFE) AF: 0.0000258 AC: 6 AN: 232934

Other (OTH) AF: 0.000115 AC: 1 AN: 8728

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

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

African (AFR) AF: 0.0000831 AC: 1 AN: 12040

American (AMR) AF: 0.000307 AC: 1 AN: 3256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1520

East Asian (EAS) AF: 0.00 AC: 0 AN: 2064

South Asian (SAS) AF: 0.00 AC: 0 AN: 1336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 26192

Other (OTH) AF: 0.00 AC: 0 AN: 606

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Benign:1

Sep 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.034
La Branchor		0.24
BranchPoint Hunter		2.0
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: rs57509953; hg19: chr3-37067099;