7-5997321-C-T

Position:

chr7-5997321-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000535.7(PMS2):c.803+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000661 in 151,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.81

Variant links:

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]

PMS2 links:

PMS2 (HGNC:):

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-5997321-C-T is Pathogenic according to our data. Variant chr7-5997321-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.803+5G>A		splice_region_variant, intron_variant		ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.803+5G>A		splice_region_variant, intron_variant		1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151364

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1251602

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

633002

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73844

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 31, 2024	The c.803+5G>A variant in the PMS2 gene is located at the canonical splice site of intron 7 and is predicted to inflict donor loss (SpliceAI delta score: 0.98), resulting in alternative splicing and disrupted protein product. The variant has been reported in individuals with colorectal/endometrial/ovarian cancer (PMID: 31992580, 38311346). Patient peripheral blood RNA RT-PCR analysis demonstrated aberrant transcripts with either partial deletion or out-of-frame skipping of exon 7 (PMID: 38311346). Other splice variants located in the same splice junction (c.803+1G>T, c.803+1G>A) have also been reported from individuals with colorectal/endometrial cancer (PMID: 3501477, 36091691, 862267). Loss-of-function variants in the PMS2 gene are known to be pathogenic (PMID: 28514183, 25512458, 35223509). This variant has been reported in ClinVar (ID: 486041). This variant is absent in the general population according to gnomAD (v4.1). Therefore, the c.803+5G>A variant in the PMS2 gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 30, 2021	The c.803+5G>A variant in PMS2 has been reported in at least 5 individuals with lynch syndrome-associated cancers (Karam 2019 PMID:31642931, Wang 2020 PMID:31992580, Ambry data). In addition, tumors sampled from 2 of these individuals showed either high microsatellite instability or lacked PMS2 expression (Wang 2020 PMID:31992580). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 486041) and has also been identified in 0.001% (1/67946) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, gnomAD v3.1.1). This variant is located in the 5' splice region and computational tools predict an impact to splicing. In vitro studies on patient RNA have shown that this variant results in abnormal splicing (Karam 2019 PMID:31642931). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Moderate, PS3_Moderate, PM2_Supporting, PP3. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2023

This sequence change falls in intron 7 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with PMS2-related conditions (PMID: 31992580; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 486041). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2024

The c.803+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 7 in the PMS2 gene. This alteration was identified as germline in conjunction with a pathogenic PMS2 somatic mutation in an individual with colorectal cancer that displayed high microsatellite instability (MSI-H) and loss of PMS2 on immunohistochemistry (IHC), but no MLH1 promoter hypermethylation was detected (Ambry internal data). Furthermore, in this family, c.803+5G>A segregated with disease in a sibling diagnosed with endometrial cancer that demonstrated loss of PMS2 on IHC (Ambry internal data). This alteration was also identified in two French patients, one with endometrial cancer that was MSI-H and the other with colorectal cancer that was MSI-H and also demonstrated loss of PMS2 on IHC (Wang Q et al. J Med Genet, 2020 07;57:487-499). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Benign

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: 5

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over