chr3-36996700-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_001167617.3(MLH1):c.-92C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,611,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

MLH1
NM_001167617.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:17

Conservation

PhyloP100: -0.579

Publications

11 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.02).

BP6

Variant 3-36996700-C-T is Benign according to our data. Variant chr3-36996700-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 89981.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167617.3. 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.198C>T	p.Thr66Thr	synonymous	Exon 2 of 19	NP_000240.1	P40692-1
MLH1	NM_001167617.3		c.-92C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 19	NP_001161089.1	P40692-3
MLH1	NM_001354620.2		c.-92C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 19	NP_001341549.1	P40692-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000458205.6	TSL:1	c.-671C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	ENSP00000402667.2	P40692-2
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.198C>T	p.Thr66Thr	synonymous	Exon 2 of 19	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.198C>T	p.Thr66Thr	synonymous	Exon 2 of 17	ENSP00000416687.3	H0Y818

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000298

AC:

AN:

251400

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000509

AC:

743

AN:

1459684

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

371

AN XY:

726308

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33434

American (AMR)

AF:

0.000380

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000139

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000610

AC:

677

AN:

1110056

Other (OTH)

AF:

0.000514

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000368

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41390

American (AMR)

AF:

0.000590

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000573

AC:

AN:

68020

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000371

Hom.:

Bravo

AF:

0.000461

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (4)

Colorectal cancer, hereditary nonpolyposis, type 2 (3)

not provided (3)

not specified (3)

Lynch syndrome (2)

Breast and/or ovarian cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Muir-Torré syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.1

(source)

DANN

Benign

0.77

PhyloP100

-0.58

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Mutation Taster

=290/10

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