3-37025629-T-TTTTTTTTA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000249.4(MLH1):c.1039-8_1039-7insTTTTTTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000030 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000046 ( 1 hom. )

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:5

Conservation

PhyloP100: 0.0980

Publications

3 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: G2P, ClinGen, Orphanet
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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, 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: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 3-37025629-T-TTTTTTTTA is Benign according to our data. Variant chr3-37025629-T-TTTTTTTTA is described in ClinVar as Benign. ClinVar VariationId is 215448.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.1039-8_1039-7insTTTTTTTA		splice_region_variant, intron_variant	Intron 11 of 18	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.1039-8_1039-7insTTTTTTTA		splice_region_variant, intron_variant	Intron 11 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes

AF:

0.0000296

AC:

AN:

135300

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000223

Gnomad FIN

AF:

0.000125

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000313

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000462

AC:

AN:

1103210

Hom.:

Cov.:

AF XY:

0.0000367

AC XY:

AN XY:

545208

show subpopulations

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

African (AFR)

AF:

0.0000474

AC:

AN:

21110

American (AMR)

AF:

0.00

AC:

AN:

17424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17586

East Asian (EAS)

AF:

0.00

AC:

AN:

29082

South Asian (SAS)

AF:

0.00

AC:

AN:

38368

European-Finnish (FIN)

AF:

0.0000271

AC:

AN:

36844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3212

European-Non Finnish (NFE)

AF:

0.0000514

AC:

AN:

895810

Other (OTH)

AF:

0.0000685

AC:

AN:

43774

⚠️ 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: 0.354

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000296

AC:

AN:

135290

Hom.:

Cov.:

AF XY:

0.0000459

AC XY:

AN XY:

65430

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33996

American (AMR)

AF:

0.00

AC:

AN:

13736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3320

East Asian (EAS)

AF:

0.00

AC:

AN:

4932

South Asian (SAS)

AF:

0.000224

AC:

AN:

4464

European-Finnish (FIN)

AF:

0.000125

AC:

AN:

7974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.0000313

AC:

AN:

63906

Other (OTH)

AF:

0.00

AC:

AN:

1826

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000197943), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.313

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:

0.000474

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MLH1 c.1039-8_1039-7insTTTTTA variant was not identified in the literature nor was it identified in dbSNP, COSMIC, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, InSiGHT Colon Cancer Gene Variant Database, Zhejiang Colon Cancer, COGR, or UMD databases. The variant was identified in the Clinvar database (classified as benign by Invitae). Clinvar also documents multiple variant deletions and insertions in this 5â€šÃ„Ã´ polynucleotide stretch as benign or likely benign. The variant was identified in control databases in 3079 of 118408 chromosomes (58 homozygous) at a frequency of 0.03, increasing the likelihood this could be a benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 524 of 5932 chromosomes (freq: 0.09), European (Non-Finnish) in 1791 of 58686 chromosomes (freq: 0.03), Other in 59 of 2174 chromosomes (freq: 0.03), East Asian in 121 of 5950 chromosomes (freq: 0.02), Finnish in 270 of 15534 chromosomes (freq: 0.02), Latino in 111 of 8698 chromosomes (freq: 0.01), South Asian in 157 of 16556 chromosomes (freq: 0.009), and Ashkenazi Jewish in 46 of 4878 chromosomes (freq: 0.009). In a study of Slovenian patients with gastric cancer, the variant IVS12 1039-7delT(n) is considered a germline polymorphism, co-occurring with pathogenic germline MLH1 mutation(s), detected in matched normal and tumour tissue of these patients (Hudler 2004). The variant occurs outside of the splicing consensus sequence and 2 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.098

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over