3-37025629-T-TTTTTTTTTTTTA

Variant names:

• chr3-37025629-T-TTTTTTTTTTTTA
• rs535965616
• NM_000249.4:c.1039-8_1039-7insTTTTTTTTTTTA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000249.4(MLH1):​c.1039-8_1039-7insTTTTTTTTTTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 3-37025629-T-TTTTTTTTTTTTA is Benign according to our data. Variant chr3-37025629-T-TTTTTTTTTTTTA is described in ClinVar as Benign. ClinVar VariationId is 215451.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.1039-8_1039-7insTTTTTTTTTTTA		splice_region intron	N/A	NP_000240.1
	MLH1	NM_001354628.2		c.1039-8_1039-7insTTTTTTTTTTTA		splice_region intron	N/A	NP_001341557.1
	MLH1	NM_001354629.2		c.940-8_940-7insTTTTTTTTTTTA		splice_region intron	N/A	NP_001341558.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1039-8_1039-7insTTTTTTTTTTTA		splice_region intron	N/A	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.1039-8_1039-7insTTTTTTTTTTTA		splice_region intron	N/A	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.1039-8_1039-7insTTTTTTTTTTTA		splice_region intron	N/A	ENSP00000416476.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 135300 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1103272 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 545244

African (AFR) AF: 0.00 AC: 0 AN: 21112

American (AMR) AF: 0.00 AC: 0 AN: 17426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17588

East Asian (EAS) AF: 0.00 AC: 0 AN: 29082

South Asian (SAS) AF: 0.00 AC: 0 AN: 38370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 895858

Other (OTH) AF: 0.00 AC: 0 AN: 43776

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 135300 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 65414

African (AFR) AF: 0.00 AC: 0 AN: 33960

American (AMR) AF: 0.00 AC: 0 AN: 13720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3320

East Asian (EAS) AF: 0.00 AC: 0 AN: 4952

South Asian (SAS) AF: 0.00 AC: 0 AN: 4486

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63916

Other (OTH) AF: 0.00 AC: 0 AN: 1812

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.098

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;