chr3-37048563-C-T

Variant names:

• chr3-37048563-C-T
• rs63750610
• NM_000249.4:c.1943C>T

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.1943C>T​(p.Pro648Leu) variant causes a missense change. 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 Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000278137: Functional studies demonstrated decreased protein expression and localization, but intact MMR function. In another study, this alteration showed a negative dominant mutator effect in yeast with MMR activity of 39.2% and MLH1 expression of 25-75% compared to wild type (Takahashi et al. Cancer Res 2007 May 15; 67(10): 4595-604).; SCV001343104: Multiple functional studies have shown that this variant causes reduced MLH1 protein expression and decreased binding to PMS2, although the variant impact on MMR activity is inconclusive (PMID:16083711, 17510385, 20020535, 20533529, 21404117, 22753075, 23403630).; SCV000952391: Experimental studies have shown that this missense change affects MLH1 function (PMID:16083711, 17510385, 20533529, 21404117, 22753075).; SCV002046193: Functional studies demonstrated decreased protein expression, localization, and MMR function (PMIDs: 16083711 (2005), 17510385 (2007), 20533529 (2010), 21404117 (2011), and 22753075 (2012)).; SCV004843242: Multiple functional studies have shown that this variant causes reduced MLH1 protein expression and decreased binding to PMS2, although the variant impact on MMR activity is inconclusive (PMID:16083711, 17510385, 20020535, 20533529, 21404117, 22753075, 23403630).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P648A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 5.88
• 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, 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

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000278137: Functional studies demonstrated decreased protein expression and localization, but intact MMR function. In another study, this alteration showed a negative dominant mutator effect in yeast with MMR activity of 39.2% and MLH1 expression of 25-75% compared to wild type (Takahashi et al. Cancer Res 2007 May 15; 67(10): 4595-604).; SCV001343104: Multiple functional studies have shown that this variant causes reduced MLH1 protein expression and decreased binding to PMS2, although the variant impact on MMR activity is inconclusive (PMID: 16083711, 17510385, 20020535, 20533529, 21404117, 22753075, 23403630).; SCV000952391: Experimental studies have shown that this missense change affects MLH1 function (PMID: 16083711, 17510385, 20533529, 21404117, 22753075).; SCV002046193: Functional studies demonstrated decreased protein expression, localization, and MMR function (PMIDs: 16083711 (2005), 17510385 (2007), 20533529 (2010), 21404117 (2011), and 22753075 (2012)).; SCV004843242: Multiple functional studies have shown that this variant causes reduced MLH1 protein expression and decreased binding to PMS2, although the variant impact on MMR activity is inconclusive (PMID: 16083711, 17510385, 20020535, 20533529, 21404117, 22753075, 23403630).
• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 30 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 chr3-37048562-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 525804.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 3-37048563-C-T is Pathogenic according to our data. Variant chr3-37048563-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 89953.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.1943C>T	p.Pro648Leu	missense	Exon 17 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354629.2		c.1844C>T	p.Pro615Leu	missense	Exon 16 of 18	NP_001341558.1	A0AAQ5BGZ2
	MLH1	NM_001354630.2		c.1778C>T	p.Pro593Leu	missense	Exon 16 of 18	NP_001341559.1	A0A669KAW3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1943C>T	p.Pro648Leu	missense	Exon 17 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000458205.6	TSL:1	c.1220C>T	p.Pro407Leu	missense	Exon 18 of 20	ENSP00000402667.2	P40692-2
	MLH1	ENST00000456676.7	TSL:1	c.1896+880C>T		intron	N/A	ENSP00000416687.3	H0Y818

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000535 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome (1)
1	-	-	Lynch syndrome 1 (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	0.69
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.89		Gain of helix (P = 0.062)
MVP		0.97
MPC		0.41
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750610; hg19: chr3-37090054; COSMIC: COSV51620534;