Genetic Variant MLH1:c.*32C>T (chr3-37050685-C-T) – 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 NM_000249.4(MLH1):c.*32C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,543,852 control chromosomes in the GnomAD database, including 10 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 0.00082 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 9 hom. )

Consequence

MLH1
NM_000249.4 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.0580

Publications

1 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

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=-0.84).

BP6

Variant 3-37050685-C-T is Benign according to our data. Variant chr3-37050685-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 135561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000817 (119/145662) while in subpopulation SAS AF = 0.00502 (24/4784). AF 95% confidence interval is 0.00346. There are 1 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD 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	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.*32C>T	3_prime_UTR	Exon 19 of 19	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.*32C>T	3_prime_UTR	Exon 18 of 18	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.*32C>T	3_prime_UTR	Exon 18 of 18	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.*32C>T	3_prime_UTR	Exon 19 of 19	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.*32C>T	3_prime_UTR	Exon 17 of 17	ENSP00000416687.3	H0Y818
MLH1	ENST00000413740.2	TSL:1	c.*32C>T	3_prime_UTR	Exon 15 of 15	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes

AF:

0.000824

AC:

120

AN:

145564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000748

Gnomad ASJ

AF:

0.00711

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00501

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0201

Gnomad NFE

AF:

0.000689

Gnomad OTH

AF:

0.00100

GnomAD2 exomes

AF:

0.00158

AC:

395

AN:

250380

AF XY:

0.00180

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000916

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00110

AC:

1537

AN:

1398190

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

893

AN XY:

696698

show subpopulations

African (AFR)

AF:

0.000128

AC:

AN:

31256

American (AMR)

AF:

0.00117

AC:

AN:

43758

Ashkenazi Jewish (ASJ)

AF:

0.00580

AC:

148

AN:

25526

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00616

AC:

523

AN:

84952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49766

Middle Eastern (MID)

AF:

0.00419

AC:

AN:

5256

European-Non Finnish (NFE)

AF:

0.000664

AC:

704

AN:

1060110

Other (OTH)

AF:

0.00147

AC:

AN:

57950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

156

235

313

391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000817

AC:

119

AN:

145662

Hom.:

Cov.:

AF XY:

0.000955

AC XY:

AN XY:

71238

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

39032

American (AMR)

AF:

0.000747

AC:

AN:

14718

Ashkenazi Jewish (ASJ)

AF:

0.00711

AC:

AN:

3374

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00502

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10080

Middle Eastern (MID)

AF:

0.0216

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000689

AC:

AN:

65346

Other (OTH)

AF:

0.000993

AC:

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000750

Hom.:

Bravo

AF:

0.000820

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Colorectal cancer, hereditary nonpolyposis, type 2 (1)

not provided (1)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.3

(source)

DANN

Benign

0.65

PhyloP100

0.058

Mutation Taster

=100/0

polymorphism

(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

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