NM_000535.7:c.1004A>G

Variant names:

• chr7-5989940-T-C
• rs200513014
• NM_000535.7:c.1004A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS1

The NM_000535.7(PMS2):​c.1004A>G​(p.Asn335Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,607,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:9 O:1
• Conservation: PhyloP100: 7.73

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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• BP6: Variant 7-5989940-T-C is Benign according to our data. Variant chr7-5989940-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127751.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=1, Uncertain_significance=12, not_provided=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000256 (39/152306) while in subpopulation NFE AF= 0.00047 (32/68026). AF 95% confidence interval is 0.000342. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1004A>G	p.Asn335Ser	missense_variant	Exon 10 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1004A>G	p.Asn335Ser	missense_variant	Exon 10 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000275 AC: 69 AN: 250652 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135496

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0000985

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000287 AC: 417 AN: 1455222 Hom.: 0 Cov.: 28 AF XY: 0.000260 AC XY: 188 AN XY: 724136

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.000416

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74468

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000845 Hom.: 0

Bravo AF: 0.000366

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000305 AC: 37

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:2

Sep 16, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28195393, 28135145, 25256751, 24549055, 24728327, 28503720, 27153395, 28596308, 28874130, 28591191, 28873162, 30306255, 27535533, 11574484, 29625052, 31992580) -

Aug 04, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 21, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.1004A>G; p.Asn335Ser variant (rs200513014) is reported in the literature in individuals with hereditary breast and/or ovarian cancer (Bonache 2018, Castera 2014, Maxwell 2016, Rummel 2017, Young 2018, Tung 2015) and in individuals with Lynch syndrome/colorectal cancer (Hansen 2017, Rossi 2017, Wang 2020, Yurgelun 2017); however, an affected relative did not carry the variant (Hansen 2017). This variant is reported in ClinVar (Variation ID: 127751). It is found in the general population with an allele frequency of 0.03% (77/282,046 alleles). The asparagine at codon 335 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.972). Based on the available information, the clinical significance of this variant is uncertain at this time. -

Jul 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4 -

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:2

Jan 06, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 12, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

There is a small physicochemical difference between asparagine and serine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.Asn335Ser variant is not predicted to disrupt the existing acceptor splice site 16bp upstream by any splice site algorithm. The p.Asn335Ser variant is not predicted to introduce a novel splice site by any splice site algorithm. For these reasons, this variant has been classified as Uncertain Significance. -

Dec 08, 2017

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 27, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2019

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. -

not specified Uncertain:3 Benign:1 Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.1004A>G, in exon 10 that results in an amino acid change, p.Asn335Ser. This sequence change has been previously described in individuals with breast, ovarian, colorectal and other cancer and solid tumors (PMID: 24549055, 30306255, 31992580, 32522261, 34371384, 32959997, 32658311, 33850299, 28874130, 33821390, 28195393, 32975687). Tumors with this variant have not shown microsatellite instability (PMID: 31391288). This sequence change has been described in the gnomAD database with a frequency of 0.04% in the European subpopulation (dbSNP rs200513014). The p.Asn335Ser change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Asn335Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asn335Ser change remains unknown at this time. -

Dec 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn335Ser variant in PMS2 has been reported in 1 individual who had underg one testing for a personal or family history of breast or ovarian cancer (Caster a 2014) and 1 healthy individual (Bodian 2014). This variant has been identified in 27/65558 (0.04%) European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP 200513014). Computational prediction tools and conservation analysis suggest that the p.Asn335Ser variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, the clinical significance of the p.Asn335Ser variant is un certain. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jun 03, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.1004A>G (p.Asn335Ser) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 250652 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1004A>G has been reported in the literature in individuals affected with different types of cancer including colorectal cancer, breast and/or ovarian cancer, pancreatic cancer, therapy-related myeloid neoplasms, and papillary thyroid cancer (e.g. Harismendy_2013, Castera_2014, Tung_2014, Maxwell_2016, Yurgelun_2017, Rummel_2017, Hansen_2017, Feliubadalo_2017, Bonache_2018, Young_2018, Akcay_2020, Uyisenga_2020, Wang_2020, Bono_2021, Dorling_2021, Krivokuca_2021, Lerner-Ellis_2021, Mio_2021, Singhal_2021). One of these studies reported that segregation analysis of the variant did not support pathogenicity (Hansen_2017). Furthermore, this variant was observed in multiple unaffected controls in a breast cancer case-control study (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. A co-occurrence with a pathogenic variant has been reported (BRIP1 c.2947delA, p.Ile983Leufs*2; Lerner-Ellis_2021). Further co-occurrences with pathogenic variants in other genes were cited by two submitters in ClinVar without providing specific information (SCV001549224.1, SCV000185908.6). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 24728327, 30306255, 34371384, 24549055, 33471991, 28050010, 28195393, 24326041, 34284872, 32885271, 27153395, 33821390, 28503720, 33850299, 25186627, 32959997, 31992580, 29945567, 28135145). Based on the evidence outlined above, the variant was classified as likely benign. -

Lynch syndrome 4 Uncertain:3

Mar 30, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 30, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jun 22, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.1004A>G (p.Asn335Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 28195393, 28874130, 28135145, 29945567, 29684080), breast cancer (PMID: 32959997, 28503720, 28591191, 30306255, 25186627), and other cancers (PMID: 24549055, 29684080). The variant did not segregate with disease in one report (PMID: 28195393). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Breast and/or ovarian cancer Uncertain:1

Apr 18, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PMS2-related disorder Uncertain:1

May 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 c.1004A>G variant is predicted to result in the amino acid substitution p.Asn335Ser. This variant has been reported many times in individuals affected with several different types of cancer including breast and/or ovarian cancer, colorectal cancer, pancreatic cancer, and individuals with Lynch syndrome (see for examples Supplementary Table S1 in Castera et al. 2014. PubMed ID: 24549055; Supplementary Table S5 in Maxwell et al. 2016. PubMed ID: 27153395; Rummel et al. 2017. PubMed ID: 28503720; reported as VUS in Huang et al. 2018. PubMed ID: 29625052; Wang et al. 2020. PubMed ID: 31992580). However, a segregation study of individuals with Lynch syndrome did not support pathogenicity for this variant (Hansen et al. 2017. PubMed ID: 28195393). Additionally a case-control study found this variant in several unaffected controls (Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.044% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations in ClinVar, ranging from a variant of uncertain significance to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127751/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch-like syndrome Uncertain:1

Jul 01, 2019

Constitutional Genetics Lab, Leon Berard Cancer Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Asn335Ser variant was identified in 6 of 1000 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, solid tumor, and colorectal cancer (Castera 2014, Hansen 2017, Le 2017, Rummel 2017, Stafford 2017, Rossi 2017). The variant was identified in our laboratory in a patient with a co-occuring pathogenic MLH1 variant suggesting that the PMS2 cp.Asn335Ser variant does not have clinical significance. The variant was also identified in the following databases: dbSNP (ID: rs200513014) as "With Uncertain significance allele", ClinVar (9x uncertain significance by LMM, GeneDx and 7 additional submitters, 1x likely benign by Ambry, and 1x as Benign by Invitae). The variant was identified in control databases in 78 of 276560 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Of note, in the European population, the variant was found in 59 of 126526 chromosomes (freq. 0.0005). The p.Asn335 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary cancer Benign:1

Jan 23, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

May 02, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: PP3 (supporting pathogenic): Revel 0.972, BS1 (strong benign): MMR: CanVIG-UK Gene-Specific Guidance BS1: MTAF = 0.0003110 [> 0.0001 (0.01%)], BS3 (supporting benign): D'Arcy BM (2022) Molecular genetics & genomic medicine: PMS2 variant results in loss of ATPase activity without compromising mismatch repair. PMID: 35189042 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	0.0074	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;.;D;.
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.5	D;D;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0060	D;D;.;.;.
Sift4G	Uncertain	0.0060	D;D;.;.;.
Polyphen		1.0	D;D;.;.;D
Vest4		0.94
MVP		0.98
MPC		0.23
ClinPred		0.73	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs200513014; hg19: chr7-6029571; COSMIC: COSV99763736;