chr3-37004444-C-T

Variant names:

• chr3-37004444-C-T
• rs63750781
• ENST00000458205.6:c.-374C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_001167618.3(MLH1):​c.-374C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000821 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV004015210: Multiple experimental studies have shown that this missense change results in an unstable protein with disrupted protein interactions and defective mismatch repair activity (PMID:11781295, 17135187, 23403630, 12810663, 11429708, 17510385, 9697702)." and additional evidence is available in ClinVar. The gene MLH1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MLH1 NM_001167618.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:33
• Conservation: PhyloP100: 5.83
• Publications: 86 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: 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

ACMG classification

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

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004015210: Multiple experimental studies have shown that this missense change results in an unstable protein with disrupted protein interactions and defective mismatch repair activity (PMID: 11781295, 17135187, 23403630, 12810663, 11429708, 17510385, 9697702).; SCV000271399: "In vitro functional studies provide some evidence that the p.Thr117Met variant is deficient in mismatch repair (Trojan 2002)."; SCV000696163: IHC showed selective loss of the MLH1 protein in tumors from patients testing positive for the variant of interest and cells containing the T117M lost the ability to repair mismatched DNA both in vivo and in vitro (Takanashi, 2007; Hinrichsen, 2016).; SCV004835271: Multiple functional studies have reported that this variant impacted in vitro mismatch repair activity (PMID: 11781295, 17135187, 17510385, 20020535, 23403630).; SCV000211084: Published functional studies demonstrate a damaging effect: abrogated or significantly reduced MMR activity, no dominant mutator effect (Shimodaira 1998, Shcherbakova 1999, Trojan 2002, Plotz 2006, Vogelsang 2009, Hinrichsen 2013, Thompson 2014); SCV000888183: Functional studies indicate this variant causes significantly reduced MLH1 protein expression and DNA mismatch repair activity (PMIDs: 11781295 (2002), 17135187 (2006), 17510385 (2007), 23403630 (2013)).; SCV000211908: Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 11429708, 11781295, 12810663, 17135187, 17510385, 23403630).; SCV000669513: Multiple functional studies have demonstrated that the T117M alteration has reduced protein expression, deficient MMR activity, inactivated hMLH1-induced dominant mutator effect, and impaired interaction with hPMS2 (Shimodaira, 1998; Jäger, 2001; Trojan, 2002; Brieger, 2002; Takahashi, 2007; Drost, 2010; Hinrichsen, 2013).; SCV000684820: Multiple functional studies have reported that this variant impacted in vitro mismatch repair activity (PMID: 11781295, 17135187, 17510385, 20020535, 23403630).; SCV000592354: Functional studies characterizing the variant demonstrated reduced mismatch repair activity and nuclear localization (Andersen_2012, Brieger 2002, Jager 2001, Trojan 2002, Takahashi 2007, Plotz 2006, Vogelsang 2009); SCV003927261: Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 11429708, 1178i295, 12810663, 17135187, 17510385, 23403630).; SCV005418109: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 3-37004444-C-T is Pathogenic according to our data. Variant chr3-37004444-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17094.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167618.3. 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.350C>T	p.Thr117Met	missense	Exon 4 of 19	NP_000240.1	P40692-1
	MLH1	NM_001167618.3		c.-374C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 19	NP_001161090.1	P40692-2
	MLH1	NM_001167619.3		c.-282C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 18	NP_001161091.1	P40692-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000458205.6	TSL:1	c.-374C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 20	ENSP00000402667.2	P40692-2
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.350C>T	p.Thr117Met	missense	Exon 4 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.350C>T	p.Thr117Met	missense	Exon 4 of 17	ENSP00000416687.3	H0Y818

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251388 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461766 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111918

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	not provided (11)
6	-	-	Lynch syndrome (6)
4	-	-	Colorectal cancer, hereditary nonpolyposis, type 2 (4)
2	-	-	Endometrial carcinoma (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Inherited MMR deficiency (Lynch syndrome) (2)
2	-	-	Lynch syndrome 1 (2)
1	-	-	Colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch-like syndrome (1)
1	-	-	Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		5.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.99
MPC		0.41
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.91
gMVP		0.94
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs63750781; hg19: chr3-37045935; COSMIC: COSV51617070; COSMIC: COSV51617070;