dbSNP rs35032294: MLH1:c.-269C>G (chr3-36993279-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000673673.2(MLH1):c.-269C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 739,108 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). The gene MLH1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0053 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 12 hom. )

Consequence

MLH1
ENST00000673673.2 5_prime_UTR

Scores

Clinical Significance

Likely benign reviewed by expert panel B:5

Conservation

PhyloP100: -1.46

Publications

8 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 links:

EPM2AIP1 (HGNC:19735): (EPM2A interacting protein 1) The EPM2A gene, which encodes laforin, is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy. The protein encoded by this gene binds to laforin, but its function is not known. This gene is intronless. [provided by RefSeq, Oct 2008]

EPM2AIP1 links:

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ACMG classification

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 support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 3-36993279-C-G is Benign according to our data. Variant chr3-36993279-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 89588.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00534 (813/152364) while in subpopulation AMR AF = 0.00875 (134/15312). AF 95% confidence interval is 0.00755. There are 3 homozygotes in GnomAd4. There are 375 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000673673.2. 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.-269C>G	upstream_gene	N/A	NP_000240.1	P40692-1
EPM2AIP1	NM_014805.4	MANE Select	c.-202G>C	upstream_gene	N/A	NP_055620.1	Q7L775
MLH1	NM_001354628.2		c.-269C>G	upstream_gene	N/A	NP_001341557.1	A0A087WX20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000673673.2		c.-269C>G	5_prime_UTR	Exon 1 of 18	ENSP00000500979.2	A0A669KAW3
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.-269C>G	upstream_gene	N/A	ENSP00000231790.3	P40692-1
EPM2AIP1	ENST00000322716.8	TSL:6 MANE Select	c.-202G>C	upstream_gene	N/A	ENSP00000406027.1	Q7L775

Frequencies

GnomAD3 genomes

AF:

0.00535

AC:

814

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00876

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00794

Gnomad OTH

AF:

0.00525

GnomAD4 exome

AF:

0.00606

AC:

3554

AN:

586744

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

1784

AN XY:

304774

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

14802

American (AMR)

AF:

0.00481

AC:

AN:

20164

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

106

AN:

14710

East Asian (EAS)

AF:

0.0000313

AC:

AN:

31962

South Asian (SAS)

AF:

0.00308

AC:

154

AN:

49960

European-Finnish (FIN)

AF:

0.00215

AC:

AN:

44718

Middle Eastern (MID)

AF:

0.00491

AC:

AN:

2240

European-Non Finnish (NFE)

AF:

0.00762

AC:

2880

AN:

377920

Other (OTH)

AF:

0.00605

AC:

183

AN:

30268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

215

431

646

862

1077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00534

AC:

813

AN:

152364

Hom.:

Cov.:

AF XY:

0.00503

AC XY:

375

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41588

American (AMR)

AF:

0.00875

AC:

134

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00331

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00794

AC:

540

AN:

68028

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

137

182

228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00488

Hom.:

Bravo

AF:

0.00584

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Colorectal cancer, hereditary nonpolyposis, type 2 (1)

Hereditary cancer-predisposing syndrome (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

7.2

(source)

DANN

Benign

0.71

PhyloP100

-1.5

PromoterAI

0.0057

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

Splicing

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