NM_000249.4:c.1039-8_1039-7insTA

Variant names:

• chr3-37025629-T-TTA
• rs535965616
• NM_000249.4:c.1039-8_1039-7insTA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000249.4(MLH1):​c.1039-8_1039-7insTA variant causes a splice region, 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, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 3-37025629-T-TTA is Benign according to our data. Variant chr3-37025629-T-TTA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 182538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

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

Ensembl Transcripts

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

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

GnomAD2 exomes AF: 0.000247 AC: 29 AN: 117468 AF XY: 0.000207

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 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

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

African (AFR) AF: 0.00370 AC: 76 AN: 20528

American (AMR) AF: 0.000577 AC: 10 AN: 17334

Ashkenazi Jewish (ASJ) AF: 0.000401 AC: 7 AN: 17458

East Asian (EAS) AF: 0.000414 AC: 12 AN: 28964

South Asian (SAS) AF: 0.000549 AC: 21 AN: 38246

European-Finnish (FIN) AF: 0.000518 AC: 19 AN: 36672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3178

European-Non Finnish (NFE) AF: 0.00120 AC: 1064 AN: 884828

Other (OTH) AF: 0.00111 AC: 48 AN: 43318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

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

African (AFR) AF: 0.00194 AC: 66 AN: 33956

American (AMR) AF: 0.0000728 AC: 1 AN: 13732

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 5 AN: 3318

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4930

South Asian (SAS) AF: 0.000224 AC: 1 AN: 4464

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.000110 AC: 7 AN: 63888

Other (OTH) AF: 0.00110 AC: 2 AN: 1826

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000733 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Breast carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)
-	-	1	MLH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.098
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: rs535965616; hg19: chr3-37067120;