rs63750809

Variant names:

• chr3-37048952-T-C
• rs63750809
• NM_000249.4:c.2038T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-37048952-T-C
• chr3-37048952-T-G
• chr3-37048952-T-A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000249.4(MLH1):​c.2038T>C​(p.Cys680Arg) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000696139: This variant has been reported in two LS families from different ethnic populations (Sheng_2008, Dominguez-Valentin_2014). Additionally, one conference abstract reported that this variant cosegregated in 12 patients from 2 LS families (Bell_2013). One functional study (Dominguez-Valentin_2014) used yeast two-hybrid and cell-free mismatch repair assays to show that p.Cys680Arg not only affects the formation of MutLalfa complex but also the MMR activity -- a strong data for a pathogenic outcome." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C680G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 3.08
• 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000696139: This variant has been reported in two LS families from different ethnic populations (Sheng_2008, Dominguez-Valentin_2014). Additionally, one conference abstract reported that this variant cosegregated in 12 patients from 2 LS families (Bell_2013). One functional study (Dominguez-Valentin_2014) used yeast two-hybrid and cell-free mismatch repair assays to show that p.Cys680Arg not only affects the formation of MutLalfa complex but also the MMR activity -- a strong data for a pathogenic outcome.; SCV000277597: The effect of this alteration on MMR function was also assessed by looking at its ability to repair a GT mismatched substrate in a cell-free mismatch repair assay. Authors found the efficiency of this alteration to be comparable to that of another well-described pathogenic MLH1 mutation. Further, a yeast-based assay showed that this alteration does not interact with PMS2 suggesting that the MMR-deficiency is caused by failure to form the essential MutLa complex (Dominguez-Valentin M et al. Mol Genet Genomic Med. 2014 Jul; 2(4):352-5).; SCV000543614: Experimental studies have shown that this missense change affects MLH1 function (PMID: 25077178).; SCV004189240: Functional studies indicate this variant impacts protein function [PMID: 25077178].
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 44 uncertain in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 3-37048952-T-C is Pathogenic according to our data. Variant chr3-37048952-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 90006.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.2038T>C	p.Cys680Arg	missense	Exon 18 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.1945T>C	p.Cys649Arg	missense	Exon 17 of 18	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.1939T>C	p.Cys647Arg	missense	Exon 17 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.2038T>C	p.Cys680Arg	missense	Exon 18 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000458205.6	TSL:1	c.1315T>C	p.Cys439Arg	missense	Exon 19 of 20	ENSP00000402667.2	P40692-2
	MLH1	ENST00000456676.7	TSL:1	c.1896+1269T>C		intron	N/A	ENSP00000416687.3	H0Y818

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000105 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Colorectal cancer, hereditary nonpolyposis, type 2 (3)
2	-	-	Lynch syndrome (2)
1	-	-	Carcinoma of colon (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.039	D
Polyphen		0.97	D
Vest4		0.93
MutPred		0.78		Gain of disorder (P = 0.0144)
MVP		0.96
MPC		0.39
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.94
Mutation Taster		=58/42	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

Other links and lift over

dbSNP: rs63750809; hg19: chr3-37090443;