Genetic Variant MLH1:p.Leu653Leu (chr3-37048579-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000249.4(MLH1):c.1959G>T(p.Leu653Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,488 control chromosomes in the GnomAD database, including 237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. L653L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0088 ( 14 hom., cov: 31)

Exomes 𝑓: 0.015 ( 223 hom. )

Consequence

MLH1
NM_000249.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:27

Conservation

PhyloP100: 0.113

Publications

23 publications found

Variant links:

COSMIC-nc: COSV51623383

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 3-37048579-G-T is Benign according to our data. Variant chr3-37048579-G-T is described in ClinVar as Benign. ClinVar VariationId is 36546.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=0.113 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00879 (1337/152180) while in subpopulation NFE AF = 0.0161 (1096/68022). AF 95% confidence interval is 0.0153. There are 14 homozygotes in GnomAd4. There are 605 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.1959G>T	p.Leu653Leu	synonymous	Exon 17 of 19	NP_000240.1	P40692-1
MLH1	NM_001354629.2		c.1860G>T	p.Leu620Leu	synonymous	Exon 16 of 18	NP_001341558.1	A0AAQ5BGZ2
MLH1	NM_001354630.2		c.1794G>T	p.Leu598Leu	synonymous	Exon 16 of 18	NP_001341559.1	A0A669KAW3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1959G>T	p.Leu653Leu	synonymous	Exon 17 of 19	ENSP00000231790.3	P40692-1
MLH1	ENST00000458205.6	TSL:1	c.1236G>T	p.Leu412Leu	synonymous	Exon 18 of 20	ENSP00000402667.2	P40692-2
MLH1	ENST00000456676.7	TSL:1	c.1896+896G>T		intron	N/A	ENSP00000416687.3	H0Y818

Frequencies

GnomAD3 genomes

AF:

0.00880

AC:

1338

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00841

AC:

2113

AN:

251238

AF XY:

0.00825

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00310

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.00832

GnomAD4 exome

AF:

0.0150

AC:

21869

AN:

1461308

Hom.:

223

Cov.:

AF XY:

0.0144

AC XY:

10504

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33474

American (AMR)

AF:

0.00405

AC:

181

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000441

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00378

AC:

202

AN:

53376

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0185

AC:

20544

AN:

1111496

Other (OTH)

AF:

0.0129

AC:

778

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

1007

2015

3022

4030

5037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.00879

AC:

1337

AN:

152180

Hom.:

Cov.:

AF XY:

0.00813

AC XY:

605

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00330

AC:

137

AN:

41538

American (AMR)

AF:

0.00353

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00340

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0161

AC:

1096

AN:

68022

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0123

Hom.:

Bravo

AF:

0.00880

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0149

EpiControl

AF:

0.0149

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Colorectal cancer, hereditary nonpolyposis, type 2 (5)

Hereditary cancer-predisposing syndrome (4)

Lynch syndrome (3)

not provided (3)

Carcinoma of colon (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome 1 (1)

Muir-Torré syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.0

(source)

DANN

Benign

0.75

PhyloP100

0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=85/15

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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