rs1800734

Variant names:

Your query was ambiguous. Multiple possible variants found:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -20 ACMG points: 0P and 20B. BA1BP4_StrongBP6_Very_Strong

The ENST00000413740.2(MLH1):c.-93G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.244 (AC=313,667) in the gnomAD database across 1,283,016 control chromosomes, including 42,875 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.539. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★).

Frequency

Genomes: 𝑓 0.23 ( 4663 hom., cov: 33)

Exomes 𝑓: 0.25 ( 38212 hom. )

Consequence

MLH1
ENST00000413740.2 5_prime_UTR

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:12

Conservation

PhyloP100: -0.737

Publications

219 publications found

Variant links:

COSMIC-nc: COSV99212309

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: Orphanet, G2P, ClinGen
Lynch syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
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

new If you want to explore the variant's impact on the transcript ENST00000413740.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar ≥3 stars benign — very strong (BP6); ClinVar germline classification: Benign/Likely Benign, 3 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5388 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000413740.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.-93G>A	upstream_gene	N/A	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.-93G>A	upstream_gene	N/A	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.-93G>A	upstream_gene	N/A	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000413740.2	TSL:1	c.-93G>A	5_prime_UTR	Exon 1 of 15	ENSP00000416476.2	H0Y806
MLH1	ENST00000673673.2		c.-93G>A	5_prime_UTR	Exon 1 of 18	ENSP00000500979.2	A0A669KAW3
MLH1	ENST00000536378.5	TSL:2	c.-725G>A	5_prime_UTR	Exon 1 of 18	ENSP00000444286.2	P40692-2

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

35278

AN:

152130

Hom.:

4667

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.328

Gnomad EAS

AF:

0.554

Gnomad SAS

AF:

0.384

Gnomad FIN

AF:

0.247

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.215

Gnomad OTH

AF:

0.260

GnomAD4 exome

AF:

0.246

AC:

278381

AN:

1130768

Hom.:

38212

Cov.:

AF XY:

0.251

AC XY:

144931

AN XY:

577786

show subpopulations

African (AFR)

AF:

0.168

AC:

4557

AN:

27162

American (AMR)

AF:

0.329

AC:

14481

AN:

44030

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

7963

AN:

24094

East Asian (EAS)

AF:

0.545

AC:

20828

AN:

38216

South Asian (SAS)

AF:

0.374

AC:

29756

AN:

79520

European-Finnish (FIN)

AF:

0.253

AC:

13376

AN:

52930

Middle Eastern (MID)

AF:

0.349

AC:

1724

AN:

4946

European-Non Finnish (NFE)

AF:

0.213

AC:

172531

AN:

810386

Other (OTH)

AF:

0.266

AC:

13165

AN:

49484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

11792

23583

35375

47166

58958

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5326

10652

15978

21304

26630

<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:

0.232

AC:

35286

AN:

152248

Hom.:

4663

Cov.:

AF XY:

0.238

AC XY:

17732

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.172

AC:

7146

AN:

41542

American (AMR)

AF:

0.274

AC:

4192

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.328

AC:

1140

AN:

3472

East Asian (EAS)

AF:

0.554

AC:

2871

AN:

5178

South Asian (SAS)

AF:

0.383

AC:

1850

AN:

4828

European-Finnish (FIN)

AF:

0.247

AC:

2620

AN:

10596

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.215

AC:

14649

AN:

68016

Other (OTH)

AF:

0.262

AC:

552

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1379

2758

4137

5516

6895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.231

Hom.:

18700

Bravo

AF:

0.234

Asia WGS

AF:

0.445

AC:

1546

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.526

AC:

64554

AN:

122812

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.585

AC:

5240

AN:

8960

Hom.:

1549

ABraOM SABE-WGS-1171

AF:

0.240

AC:

561

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Colorectal cancer, hereditary nonpolyposis, type 2 (2)

Lynch syndrome (2)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Hereditary nonpolyposis colorectal neoplasms (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

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.6

(source)

DANN

Benign

0.77

PhyloP100

-0.74

PromoterAI

0.016

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over