dbSNP rs63751657: MLH1:p.Ser577Ser (chr3-37042331-G-A) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM2PP3PP5_Very_Strong

The NM_000249.4(MLH1):c.1731G>A(p.Ser577Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV004847552: In vitro and in vivo functional studies support an impact on protein function, due to out-of-frame exon skipping (Auclair 2006, Tournier 2008, Kohonen-Corish 1996, Betz 2010, Pagenstecher 2006, De Lellis 2013)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S577S) has been classified as Likely pathogenic. The gene MLH1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MLH1
NM_000249.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9900

Clinical Significance

Pathogenic reviewed by expert panel P:19U:1O:1

Conservation

PhyloP100: 0.502

Publications

42 publications found

Variant links:

COSMIC-nc: COSV51613969

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: Pathogenic. The variant received 15 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004847552: In vitro and in vivo functional studies support an impact on protein function, due to out-of-frame exon skipping (Auclair 2006, Tournier 2008, Kohonen-Corish 1996, Betz 2010, Pagenstecher 2006, De Lellis 2013).; SCV000187084: This mutation has been shown in multiple RNA studies to result in skipping of coding exon 15, which is predicted to lead to a translational frameshift (Kohonen-Corish M et al. Am. J. Hum. Genet. 1996 Oct;59(4):818-24; Auclair J et al. Hum. Mutat. 2006 Feb;27(2):145-54; Pagenstecher C et.al. Hum. Genet. 2006 Mar;119:9-22; Tournier I et al. Hum. Mutat. 2008 Dec;29(12):1412-24; Ambry internal data).; SCV000689835: Functional studies using RNA derived from carrier individuals have shown that this variant causes a complete out-of-frame skipping of exon 15 and results in a premature protein truncation. PMID: 16341550, 16395668, 19669161; SCV000601363: This variant was shown to interfere with normal MLH1 mRNA splicing (PMIDs: 19669161 (2010), 18561205 (2008), 16341550 (2006)).; SCV000284029: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16341550, 16451135, 18561205).; SCV001434926: "functional study showed that this variant causes exon 15 skipping". PMID:18561205; SCV002318445: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16341550, 18561205, 16451135).; SCV004018160: Functional studies indicate this variant impacts protein function [PMID: 16341550].; SCV005362253: Functional studies have shown that this variant results in the skipping of exon 15 (Kurzawski et al. 2006. PubMed ID: 16451135; Pagenstecher et al. 2006. PubMed ID: 16341550; Tournier et al. 2008. PubMed ID: 18561205).

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 3-37042331-G-A is Pathogenic according to our data. Variant chr3-37042331-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 89857.Status of the report is reviewed_by_expert_panel, 3 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.1731G>A	p.Ser577Ser	splice_region synonymous	Exon 15 of 19	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.1731G>A	p.Ser577Ser	splice_region synonymous	Exon 15 of 18	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.1632G>A	p.Ser544Ser	splice_region synonymous	Exon 14 of 18	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1731G>A	p.Ser577Ser	splice_region synonymous	Exon 15 of 19	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.1731G>A	p.Ser577Ser	splice_region synonymous	Exon 15 of 17	ENSP00000416687.3	H0Y818
MLH1	ENST00000458205.6	TSL:1	c.1008G>A	p.Ser336Ser	splice_region synonymous	Exon 16 of 20	ENSP00000402667.2	P40692-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443524

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719466

African (AFR)

AF:

0.00

AC:

AN:

33098

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

85890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095330

Other (OTH)

AF:

0.00

AC:

AN:

59788

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000429

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Colorectal cancer, hereditary nonpolyposis, type 2 (4)

Lynch syndrome (3)

Hereditary cancer-predisposing syndrome (2)

Breast and/or ovarian cancer (1)

Colon cancer (1)

Hereditary nonpolyposis colon cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

MLH1-related disorder (1)

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 (1)

Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=56/44

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.92

Splicevardb

3.0

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.63

Position offset: 0

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