rs267608153

chr7-5995534-C-Achr7-5995534-C-Gchr7-5995534-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000535.7(PMS2):c.903G>T(p.Lys301Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000658 in 152,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K301E) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PMS2 NM_000535.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 3.87

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000535.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-5995534-C-A is Pathogenic according to our data. Variant chr7-5995534-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91377.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5995534-C-A is described in Lovd as [Pathogenic]. Variant chr7-5995534-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.903G>T	p.Lys301Asn	missense_variant, splice_region_variant	8/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.903G>T	p.Lys301Asn	missense_variant, splice_region_variant	8/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251238 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74256

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 28, 2016	The PMS2 c.903G>T (p.Lys301Asn) missense variant has been reported in a heterozygous state in three unrelated individuals affected with a Lynch syndrome-associated tumor and showing isolated loss of PMS2 by immunohistochemistry (Senter et al. 2008). In addition, Suerink et al. (2016) reported three heterozygous carriers of the p.Lys301Asn variant from one family, wherein at least one individual was affected. The p.Lys301Asn variant was absent from 80 controls (Tomsic et al. 2013) and is reported at a frequency of 0.00009 in the Latino population of the Exome Aggregation Consortium, though this is based on only one allele in a region of good sequencing coverage. Functional studies used RT-PCR analyses of patient RNA as well as minigene assays to demonstrate that the p.Lys301Asn variant caused an out of frame skipping of exon 8 (van der Klift et al. 2015). Based on the evidence, the p.Lys301Asn variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 19, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 26247049, 27435373]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 09, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2021	The PMS2 c.903G>T (p.Lys301Asn) variant is located at the last nucleotide of exon 8, and experimental studies have shown this variant causes skipping of exon 8, resulting in a frameshift and premature termination of PMS2 protein synthesis or absent mRNA expression (PMIDs: 26247049 (2015), 26110232 (2016)). In addition, the variant has been reported in individuals/families with Lynch syndrome-associated cancers (PMIDs: 27435373 (2016), 26110232 (2016), 25512458 (2015), 22577899 (2013), 18602922 (2008)). It has also been reported in an individual with CMMRD (PMID: 26318770 (2015)). The frequency of this variant in the general population, 0.000029 (1/34578 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2023	Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing predicted to cause protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Suerink et al., 2016; van der Klift et al., 2015; van der Klift et al., 2016); Observed in multiple individuals with personal or family histories of Lynch syndrome-associated cancers, many who had tumors that exhibited high microsatellite instability and/or abnormal PMS2 protein expression on immunohistochemistry (Senter et al., 2008; Goodenberger et al., 2016; Suerink et al., 2016; Martin-Morales et al., 2018; Wang et al., 2020); Observed in a patient with constitutional mismatch repair deficiency syndrome (CMMRD) in published literature, however a second pathogenic variant was not noted (Lavoine et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25856668, 32549215, 29922827, 28888541, 22577899, 18602922, 25512458, 26110232, 26269718, 25345868, 11574484, 26247049, 32571878, 30256826, 30787465, 31332305, 27435373, 31992580, 26318770) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	This variant causes a G>T nucleotide substitution at the end of exon 8 in the PMS2 gene. Splice site prediction tools predicted RNA splicing impact at the intron 8 splice donor site. Functional RNA studies reported the variant transcript has complete skipping of exon 8 (r.804_903del and p.Tyr268*) as detected by RT-PCR on patient-derived RNA and corroborated in RNA assays (PMID: 26247049, 27435373, 31332305). This variant has been reported in multiple individuals with personal or family history of Lynch syndrome-associated cancer (PMID: 18602922, 25512458, 25856668, 26110232, 30256826), including tumor samples that showed microsatellite instability and loss of DNA mismatch repair protein (InSiGHT). This variant has also been reported in an individual diagnosed with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 26318770). This variant has been identified in 1/251238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 2021	The c.903G>T pathogenic mutation (also known as p.K301N), located in coding exon 8 of the PMS2 gene, results from a G to T substitution at nucleotide position 903. The lysine at codon 301 is replaced by asparagine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in multiple individuals with personal and/or family histories consistent with Lynch syndrome (Goodenberger ML et al. Genet. Med., 2016 Jan;18:13-9; Suerink M et al. Genet. Med., 2016 Apr;18:405-9; ten Broeke SW et al. J. Clin. Oncol., 2015 Feb;33:319-25; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885) and several had isolated loss of PMS2 staining on immunohistochemistry in their Lynch-associated tumors (Senter L et al. Gastroenterology. 2008 August;135(2):419-28; Tomsic J et al. Clin. Genet. 2013 Mar; 83(3):238-43; van der Klift HM et al. Mol. Genet. Genomic Med 2015 Jul; 3(4):327-45). RNA studies have demonstrated that this alteration results in skipping of coding exon 8 (Ambry internal data; van der Klift HM et al. Mol. Genet. Genomic Med 2015 Jul; 3(4):327-45). One French individual diagnosed with constitutional mismatch repair deficiency syndrome (CMMRD) was found to carry the c.903G>T mutation in conjunction with another PMS2 pathogenic mutation (Lavoine N et al. J. Med. Genet., 2015 Nov;52:770-8). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

G>non-G at last base of exon with 6 bases of the intron not GTRRGT (splicing aberration has not been quantified) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 301 of the PMS2 protein (p.Lys301Asn). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs267608153, gnomAD 0.003%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency (CMMR-D) syndrome and Lynch syndrome-related cancers (PMID: 18602922, 25856668, 26110232, 26318770, 27435373; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 91377). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;.;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D;D;.;.;.
REVEL	Uncertain	0.63
Sift	Benign	0.072	T;T;.;.;.
Sift4G	Benign	0.18	T;T;.;.;.
Polyphen		1.0	D;D;.;.;D
Vest4		0.70
MutPred		0.62		Loss of ubiquitination at K301 (P = 0.0297);.;.;.;.;
MVP		0.92
MPC		0.26
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.66
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.72		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608153; hg19: chr7-6035165;