dbSNP rs57509953: MLH1:c.1039-16_1039-8delTTTTTTTTT (chr3-37025608-ATTTTTTTTT-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000249.4(MLH1):c.1039-16_1039-8delTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene MLH1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.781

Publications

1 publications found

Variant links:

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: ClinGen, Orphanet, G2P
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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, 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

MLH1 links:

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ACMG classification

Specifications for MLH1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.1039-16_1039-8delTTTTTTTTT	splice_region intron	N/A	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.1039-16_1039-8delTTTTTTTTT	splice_region intron	N/A	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.940-16_940-8delTTTTTTTTT	splice_region intron	N/A	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1039-28_1039-20delTTTTTTTTT	intron	N/A	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.1039-28_1039-20delTTTTTTTTT	intron	N/A	ENSP00000416687.3	H0Y818
MLH1	ENST00000413740.2	TSL:1	c.1039-28_1039-20delTTTTTTTTT	intron	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

258468

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128320

African (AFR)

AF:

0.00

AC:

AN:

3344

American (AMR)

AF:

0.00

AC:

AN:

1274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2090

East Asian (EAS)

AF:

0.00

AC:

AN:

3044

South Asian (SAS)

AF:

0.00

AC:

AN:

5298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

526

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

232940

Other (OTH)

AF:

0.00

AC:

AN:

8730

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.78

La Branchor

0.24

BranchPoint Hunter

2.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over