7-5997426-GAAAAAAA-GAAAAAAAAA

Variant names:

• chr7-5997426-G-GAA
• rs60794673
• NM_000535.7:c.706-5_706-4dupTT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_000535.7(PMS2):​c.706-5_706-4dupTT 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 0.00019 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0032 (0 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.187

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 7-5997426-G-GAA is Benign according to our data. Variant chr7-5997426-G-GAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1802741.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00322 (3116/967390) while in subpopulation AMR AF= 0.00394 (128/32520). AF 95% confidence interval is 0.00362. There are 0 homozygotes in gnomad4_exome. There are 1525 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.706-5_706-4dupTT		splice_region_variant, intron_variant	Intron 6 of 14	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.706-4_706-3insTT		splice_region_variant, intron_variant	Intron 6 of 14	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 25 AN: 133228 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000137

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000287

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00322 AC: 3116 AN: 967390 Hom.: 0 Cov.: 0 AF XY: 0.00308 AC XY: 1525 AN XY: 495440

Gnomad4 AFR exome AF: 0.00360

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.000807

Gnomad4 EAS exome AF: 0.000413

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00148

Gnomad4 NFE exome AF: 0.00374

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.000188 AC: 25 AN: 133270 Hom.: 0 Cov.: 0 AF XY: 0.000188 AC XY: 12 AN XY: 63804

Gnomad4 AFR AF: 0.000114

Gnomad4 AMR AF: 0.000152

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000137

Gnomad4 NFE AF: 0.000287

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome Uncertain:1

May 17, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Apr 29, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Benign:1

Nov 01, 2018

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Oct 31, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs60794673; hg19: chr7-6037057;