rs587779338

chr7-5977589-G-Achr7-5977589-G-Cchr7-5977589-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_000535.7(PMS2):c.2444C>T(p.Ser815Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 15/22 in silico tools predict a damaging outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S815S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense, splice_region
• Scores: Splicing: ADA: 0.9872
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11 U:1
• Conservation: PhyloP100: 9.99

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_pathogenic. Variant got 9 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-5977589-G-A is Pathogenic according to our data. Variant chr7-5977589-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91343.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5977589-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-5977589-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2444C>T	p.Ser815Leu	missense_variant, splice_region_variant	14/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2444C>T	p.Ser815Leu	missense_variant, splice_region_variant	14/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3 AN: 148602 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.0000492

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: 0.0000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000100 AC: 2 AN: 199430 Hom.: 0 AF XY: 0.00000918 AC XY: 1 AN XY: 108984

Gnomad AFR exome AF: 0.0000828

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000366

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000299 AC: 42 AN: 1402354 Hom.: 0 Cov.: 29 AF XY: 0.0000300 AC XY: 21 AN XY: 698944

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000357

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000292

Gnomad4 OTH exome AF: 0.0000343

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000202 AC: 3 AN: 148602 Hom.: 0 Cov.: 30 AF XY: 0.0000277 AC XY: 2 AN XY: 72266

Gnomad4 AFR AF: 0.0000492

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: 0.0000150

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000846 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Oct 18, 2018	Abrogated MMR activity in 2 independent labs, 4 MSI-H/IHC loss tumors, MAF<0.01, 1 Ams family with 2 non-proband affected carriers. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 24, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2019	The p.Ser815Leu variant in PMS2 has been reported in the heterozygous state in at least 3 individuals with PMS2-related cancers and segregated with disease in 2 affected members of one family (van der Klift 2010, Brea-Fernández 2014, ten Broeke 2015, van der Klift 2016, González-Acosta 2017). It has also been reported in the homozygous or compound heterozygous state in 2 individuals with features of congenital mismatch repair deficiency (CMMRD) and absence of PMS2 protein by IHC (Suerink 2016 and 2018, University of Washington personal communication). This variant has been identified in 0.008% (1/12702) of African chromosomes in gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies suggest that this variant leads to reduced PMS2 protein levels and deficiencies in mismatch repair (van der Klift 2016, González-Acosta 2017). Computational prediction tools and conservation analyses support that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Finally, this variant was classified as Likely Pathogenic on Oct. 18, 2018 by the ClinGen-approved InSiGHT expert panel (SCV000108351.3). 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: PM3, PS3_Moderate, PP3, PS4_Supporting. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2022	Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (van der Klift et al., 2016); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene and has been shown to segregate with affected individuals in one family (van der Klift et al., 2010; Suerink et al., 2016; ten Broeke et al., 2015; Gonzalez-Acosta et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26110232, 23837913, 25512458, 22675565, 22290698, 20186688, 23709753, 27435373, 23435383, 30013564, 28365877, Lukas2018, 28503822, 21552516, 29922827, 35451539, 35532657) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2023	The p.S815L variant (also known as c.2444C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2444. The serine at codon 815 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in several individuals with Lynch associated cancers that demonstrated high microsatellite instability (MSI-H) and/or loss of PMS2 on immunohistochemistry (IHC) (van der Klift HM et al. Hum. Mutat. 2010 May;31:578-87; van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179). It has also been reported in a homozygous state in a child with features of CMMRD and demonstrated severely impaired mismatch activity in an in vitro functional assay (van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179; Suerink M et al. Clin. Genet. 2018 Jan;93:134-137). This alteration was also identified in three affected individuals of a family that met Amsterdam II criteria, and the colorectal tumor of the proband as well as the ovarian tumor of the mother showed MSI-H with loss of PMS2 on IHC (Brea-Fernández AJ et al. Clin. Genet. 2014 Jun;85:583-8; Gonzalez-Acosta M et al. Fam. Cancer 2017 Oct;16(4):501-507). Additional in vitro functional assays demonstrated decreased MLH1 and PMS2 protein expression as well as impaired MMR activity for the p.S815L variant (Gonzalez-Acosta M et al. Fam. Cancer 2017 Oct;16(4):501-507). Based on internal structural assessment, this alteration is expected to disrupt the interaction of PMS2 with MLH1 (Ambry internal data; Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr;20:461-8). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 25, 2023	This missense variant replaces serine with leucine at codon 815 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional assays have reported that this variant protein have significantly reduced mismatch repair activity and protein expression compared to wild type (PMID: 27435373, 28365877). This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancers (PMID: 20186688, 23837913, 25512458, 26110232, 27435373, 28365877; https://www.lovd.nl/), and has been observed to segregate with disease in one family (PMID: 28365877). This variant has also been observed in a homozygous carrier affected with constitutional mismatch repair deficiency (PMID: 28503822). This variant has been identified in 2/199430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Lynch syndrome 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 25, 2023	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 27435373]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 24, 2022

Variant summary: PMS2 c.2444C>T (p.Ser815Leu) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1e-05 in 199430 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with colorectal cancer and other Lynch Syndrome related tumors (Brea-Fernandez_2013 , Gonzalez-Acosta_2017, van der Klift_2016). In one family the variant co-segregated with the disease (Gonzalez-Acosta_2017). The variant has also reported in the homozygous state in an individual with constitutional mismatch repair deficiency (Suerink_2017). Experimental evidence suggest that this variant significantly reduce mismatch repair activity and protein expression in vitro (Gonzalez-Acosta_2017, van der Klift_2016). Taken together, these data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 815 of the PMS2 protein (p.Ser815Leu). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with Lynch syndrome (PMID: 20186688, 23837913, 25512458, 26110232, 27435373, 28503822; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91343). An algorithm developed specifically for the PMS2 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). Experimental studies have shown that this missense change affects PMS2 function (PMID: 27435373, 28365877). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;.;.;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;D;.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.3	D;D;.;.;.;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.99
MVP		0.95
MPC		2.9
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.0		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: rs587779338; hg19: chr7-6017220; COSMIC: COSV56219453; COSMIC: COSV56219453;