3-37025608-ATTTTTTTTT-ATTTTTTTTTTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000249.4(MLH1):c.1039-9_1039-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0024 ( 2 hom. )

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0340

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

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 3-37025608-A-ATT is Benign according to our data. Variant chr3-37025608-A-ATT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 413381.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0022 (106/48268) while in subpopulation SAS AF = 0.00374 (5/1336). AF 95% confidence interval is 0.00213. There are 2 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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	Effect	Exon Rank	Protein	UniProt
MLH1	NM_000249.4	MANE Select	c.1039-9_1039-8dupTT	splice_region intron	N/A	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.1039-9_1039-8dupTT	splice_region intron	N/A	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.940-9_940-8dupTT	splice_region intron	N/A	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1039-29_1039-28insTT	intron	N/A	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.1039-29_1039-28insTT	intron	N/A	ENSP00000416687.3	H0Y818
MLH1	ENST00000413740.2	TSL:1	c.1039-29_1039-28insTT	intron	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes

AF:

0.00220

AC:

106

AN:

48280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00216

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00369

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00337

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00658

GnomAD4 exome

AF:

0.00236

AC:

609

AN:

257724

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

287

AN XY:

127930

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00600

AC:

AN:

3336

American (AMR)

AF:

0.00236

AC:

AN:

1272

Ashkenazi Jewish (ASJ)

AF:

0.00338

AC:

AN:

2072

East Asian (EAS)

AF:

0.00198

AC:

AN:

3028

South Asian (SAS)

AF:

0.00322

AC:

AN:

5286

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1220

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

522

European-Non Finnish (NFE)

AF:

0.00229

AC:

533

AN:

232288

Other (OTH)

AF:

0.00253

AC:

AN:

8700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.348

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00220

AC:

106

AN:

48268

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

AN XY:

21490

show subpopulations

African (AFR)

AF:

0.00216

AC:

AN:

12034

American (AMR)

AF:

0.00369

AC:

AN:

3256

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

1520

East Asian (EAS)

AF:

0.00339

AC:

AN:

2062

South Asian (SAS)

AF:

0.00374

AC:

AN:

1336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

26190

Other (OTH)

AF:

0.00658

AC:

AN:

608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast and/or ovarian cancer (1)

Hereditary cancer-predisposing syndrome (1)

Hereditary nonpolyposis colorectal neoplasms (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.034

La Branchor

0.24

BranchPoint Hunter

2.0

Mutation Taster

=100/0

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