3-37012071-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS3BS1BP5

This summary comes from the ClinGen Evidence Repository: The NM_000249.4(MLH1):c.649C>T (p.Arg217Cys) variant is a missense variant predicted to cause substitution of Arginine by Cystein at amino acid 217 (p.Arg217Cys). The allele frequency of the variant c.649C>T is 0.3% (PopMax Filtering AF 0.0037 in East Asian Population) for the total non-cancer dataset from gnomAD (v2.1.1), and gnomAD v4.1 Grpmax AF is 0.003970 which is higher than the ClinGen InSiGHT MMR VCEP threshold (≥ 0.001 or 0,1%) for BS1, and therefore meets this criterion (BS1).The CIMRA Functional Odds for Pathogenicity is 0.01 which is below the VCEP threshold of ≤ 0.052 (BS3 met).Also the variant has been detected in 2 or 3 tumours: CRC/Endometrial tumours with MSS and/or no loss of MMR protein expression and/or LS spectrum tumoursf with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation (BP5 met).In summary, this variant meets the criteria to be classified as benign for autosomal-dominant inherited Lynch syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP : criteria BS2, BS3 and BP5 applied. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA011361/MONDO:0007356/115

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MLH1
NM_001167618.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:13

Conservation

PhyloP100: 2.99

Publications

62 publications found

Variant links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.649C>T	p.Arg217Cys	missense	Exon 8 of 19	NP_000240.1	P40692-1
MLH1	NM_001167618.3		c.-75C>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 19	NP_001161090.1	P40692-2
MLH1	NM_001167619.3		c.-75C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 18	NP_001161091.1	P40692-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000458205.6	TSL:1	c.-75C>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 20	ENSP00000402667.2	P40692-2
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.649C>T	p.Arg217Cys	missense	Exon 8 of 19	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.649C>T	p.Arg217Cys	missense	Exon 8 of 17	ENSP00000416687.3	H0Y818

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000370

AC:

AN:

251150

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00468

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

200

AN:

1461518

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00451

AC:

179

AN:

39690

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111684

Other (OTH)

AF:

0.0000828

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00212

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hereditary cancer-predisposing syndrome (3)

Colorectal cancer, hereditary nonpolyposis, type 2 (2)

not specified (2)

Carcinoma of colon (1)

Hereditary breast ovarian cancer syndrome (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome 1 (1)

MLH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.14

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.6

PhyloP100

3.0

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.2

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.85

MVP

0.98

MPC

0.46

ClinPred

0.28

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.82

Mutation Taster

=216/84

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over