rs267607894

Variant names:

• chr3-37050628-T-C
• rs267607894
• NM_000249.4:c.2246T>C
• MLH1 p.Leu749Pro

Your query was ambiguous. Multiple possible variants found:

• chr3-37050628-T-C
• chr3-37050628-T-G
• chr3-37050628-T-A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000249.4(MLH1):​c.2246T>C​(p.Leu749Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: "SCV000278167: Authors suggest the pathogenic effect of this mutation is due to direct interference with dimerization and severely compromised mismatch repair activity (Kosinski J et al. Hum Mutat. 2010 Aug" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L749V) has been classified as Likely pathogenic. The gene MLH1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 7.81
• Publications: 20 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, G2P, 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, G2P, Orphanet, Ambry Genetics
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, 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

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

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000278167: Authors suggest the pathogenic effect of this mutation is due to direct interference with dimerization and severely compromised mismatch repair activity (Kosinski J et al. Hum Mutat. 2010 Aug; 31(8):975-82). In another study, cells with the MLH1 p.L749P pathogenic mutation had protein expression levels of greater than 70% when compared to wild-type; however the repair activity was less than 30% when compared to wild-type (Hinrichsen I et al. Clin Cancer Res. 2013 May; 19(9):2432-41).; SCV000905472: Functional studies have shown that this variant decreases protein stability and impairs DNA mismatch repair activity (PMID: 20533529, 22736432, 23403630, 28767177).; SCV000565172: Published functional studies demonstrate a damaging effect: reduced mismatch repair activity compared to wild-type and decreased PMS2 levels suggesting a defect in the MLH1-PMS2 heterodimer, with inconsistent results with respect to MLH1 protein expression (PMID: 20533529, 22736432, 23403630); SCV000543529: Experimental studies have shown that this missense change affects MLH1 function (PMID: 20533529, 22736432, 23403630).; SCV001550087: "The variant caused decreased co-expression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that this alteration may confer a pathogenic effect (Kosinski 2010, Borras 2012, Dudley 2015). The variant also severely compromised mismatch repair activity (Kosinski 2010)."; SCV002072850: Experimental studies have shown that this missense change affects MLH1 function (Kosinski et al., 2010; Borràs et al., 2012).; SCV004186498: Functional studies indicate this variant impacts protein function [PMID: 23403630, 22736432, 20533529].; SCV005338551: Functional studies have shown this variant negatively impacts protein function (Kosinski J et al. 2010. PubMed ID: 20533529; Hinrichsen I et al. 2013. PubMed ID: 23403630; Borràs E et al. 2012. PubMed ID: 22736432).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 34 uncertain in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-37050627-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3635666.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-37050628-T-C is Pathogenic according to our data. Variant chr3-37050628-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 90097.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.2246T>C	p.Leu749Pro	missense	Exon 19 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.2153T>C	p.Leu718Pro	missense	Exon 18 of 18	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.2147T>C	p.Leu716Pro	missense	Exon 18 of 18	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.2246T>C	p.Leu749Pro	missense	Exon 19 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.2039T>C	p.Leu680Pro	missense	Exon 17 of 17	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.1810T>C	p.Tyr604His	missense	Exon 15 of 15	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000534 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Colorectal cancer, hereditary nonpolyposis, type 2 (3)
3	-	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Carcinoma of colon (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Inherited MMR deficiency (Lynch syndrome) (1)
1	-	-	Lynch syndrome (1)
1	-	-	MLH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.99
gMVP		0.96
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs267607894;

hg19: chr3-37092119;