rs1229860023

Variant names:

• chr7-5997426-G-A
• rs1229860023
• NM_000535.7:c.706-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-5997426-G-A
• chr7-5997426-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000535.7(PMS2):​c.706-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Scores: Splicing: ADA: 0.001167
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.125

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-5997426-G-A is Benign according to our data. Variant chr7-5997426-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 492288.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr7-5997426-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000174 (169/969870) while in subpopulation AFR AF= 0.000584 (13/22262). AF 95% confidence interval is 0.00038. There are 0 homozygotes in gnomad4_exome. There are 73 alleles in male gnomad4_exome subpopulation. Median coverage is 15. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.706-3C>T		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.706-3C>T		splice_region_variant, intron_variant	Intron 6 of 14	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00 AC: 17 AN: 133190 Hom.: 0 Cov.: 22 FAILED QC

Gnomad AFR AF: 0.0000860

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000759

Gnomad ASJ AF: 0.000310

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000550

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000128

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 169 AN: 969870 Hom.: 0 Cov.: 15 AF XY: 0.000147 AC XY: 73 AN XY: 496728

Gnomad4 AFR exome AF: 0.000584

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.000190

Gnomad4 EAS exome AF: 0.0000884

Gnomad4 SAS exome AF: 0.0000898

Gnomad4 FIN exome AF: 0.000266

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.0000697

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000128 AC: 17 AN: 133234 Hom.: 0 Cov.: 22 AF XY: 0.000172 AC XY: 11 AN XY: 63794

Gnomad4 AFR AF: 0.0000858

Gnomad4 AMR AF: 0.0000759

Gnomad4 ASJ AF: 0.000310

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000550

Gnomad4 NFE AF: 0.000128

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Jun 02, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jun 28, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 6 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 492288). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Jul 20, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.9
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1229860023; hg19: chr7-6037057; COSMIC: COSV105056450; COSMIC: COSV105056450;