3-37025629-TA-TAA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_000249.4(MLH1):​c.1039-6dup variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 19)
Exomes 𝑓: 0.00052 ( 1 hom. )
Failed GnomAD Quality Control

Consequence

MLH1
NM_000249.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0980
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6
Variant 3-37025629-T-TA is Benign according to our data. Variant chr3-37025629-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 140797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000606 (82/135212) while in subpopulation AFR AF= 0.00127 (43/33962). AF 95% confidence interval is 0.000966. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH1NM_000249.4 linkuse as main transcriptc.1039-6dup splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000231790.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.1039-6dup splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_000249.4 P1P40692-1

Frequencies

GnomAD3 genomes
AF:
0.000606
AC:
82
AN:
135222
Hom.:
0
Cov.:
19
show subpopulations
Gnomad AFR
AF:
0.00127
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000510
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000404
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000470
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000153
AC:
18
AN:
117468
Hom.:
0
AF XY:
0.000133
AC XY:
9
AN XY:
67558
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000411
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000243
Gnomad FIN exome
AF:
0.000135
Gnomad NFE exome
AF:
0.000173
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000521
AC:
571
AN:
1096034
Hom.:
1
Cov.:
20
AF XY:
0.000537
AC XY:
291
AN XY:
541536
show subpopulations
Gnomad4 AFR exome
AF:
0.00169
Gnomad4 AMR exome
AF:
0.000346
Gnomad4 ASJ exome
AF:
0.000342
Gnomad4 EAS exome
AF:
0.000345
Gnomad4 SAS exome
AF:
0.000157
Gnomad4 FIN exome
AF:
0.000272
Gnomad4 NFE exome
AF:
0.000532
Gnomad4 OTH exome
AF:
0.000552
GnomAD4 genome
AF:
0.000606
AC:
82
AN:
135212
Hom.:
0
Cov.:
19
AF XY:
0.000566
AC XY:
37
AN XY:
65400
show subpopulations
Gnomad4 AFR
AF:
0.00127
Gnomad4 AMR
AF:
0.000510
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000406
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000470
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00142
Hom.:
0

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 18, 2014This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 31, 2019- -
Likely benign, criteria provided, single submittercurationSema4, Sema4Jun 07, 2021- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJun 08, 2020- -
Carcinoma of colon Benign:1
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The MLH1 c.1039-6dupA variant was identified in dbSNP (ID: rs535965616) as “Benign ,Likely benign, Uncertain significance allele”, Clinvitae database (as Benign), ClinVar database (as Benign, by GeneDx, Ambry and Invitae), the 1000 Genomes Project in 239 of 5008 chromosomes (frequency: 0.047), the Exome Aggregation Consortium database (August 8, 2016) in 1441 (49 homozygous) of 43560 chromosomes (frequency: 0.033) in the following populations: African in 282 of 3072 chromosomes (frequency: 0.091), European in 838 of 21102 chromosomes (frequency: 0.039), Finnish in 75 of 2195 chromosomes (frequency: 0.034), East Asian in 80 of 2738 chromosomes (frequency: 0.029), other in 10 of 354 chromosomes (frequency: 0.028), Latino in 60 of 3678 chromosomes (frequency: 0.01.6 x 10-2) and South Asian in 96 of 10422 chromosomes (frequency: 0.0009). This variant was not identified in the literature nor was it identified in COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database, UMD and the NHLBI GO Exome Sequencing Project databases. The c.1039-6dupA variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; in addition 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJun 09, 2018- -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553650466; hg19: chr3-37067120; API