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NM_000535.7(PMS2):c.108C>A (p.Ser36Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Oct 21, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001017239.6

Allele description [Variation Report for NM_000535.7(PMS2):c.108C>A (p.Ser36Arg)]

NM_000535.7(PMS2):c.108C>A (p.Ser36Arg)

Gene:
PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p22.1
Genomic location:
Preferred name:
NM_000535.7(PMS2):c.108C>A (p.Ser36Arg)
HGVS:
  • NC_000007.14:g.6005947G>T
  • NG_008466.1:g.8160C>A
  • NG_050738.1:g.1697G>T
  • NM_000535.7:c.108C>AMANE SELECT
  • NM_001322003.2:c.-298C>A
  • NM_001322004.2:c.-242-1889C>A
  • NM_001322005.2:c.-298C>A
  • NM_001322006.2:c.108C>A
  • NM_001322007.2:c.-108C>A
  • NM_001322008.2:c.-52-1889C>A
  • NM_001322009.2:c.-298C>A
  • NM_001322010.2:c.-242-1889C>A
  • NM_001322011.2:c.-777C>A
  • NM_001322012.2:c.-777C>A
  • NM_001322013.2:c.-298C>A
  • NM_001322014.2:c.108C>A
  • NM_001322015.2:c.-377C>A
  • NP_000526.2:p.Ser36Arg
  • NP_001308935.1:p.Ser36Arg
  • NP_001308943.1:p.Ser36Arg
  • LRG_161t1:c.108C>A
  • LRG_161:g.8160C>A
  • NC_000007.13:g.6045578G>T
  • NM_000535.5:c.108C>A
  • NM_000535.6:c.108C>A
  • NR_136154.1:n.195C>A
Protein change:
S36R
Links:
dbSNP: rs1368578377
NCBI 1000 Genomes Browser:
rs1368578377
Molecular consequence:
  • NM_001322003.2:c.-298C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322005.2:c.-298C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322007.2:c.-108C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322009.2:c.-298C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322011.2:c.-777C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322012.2:c.-777C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322013.2:c.-298C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322015.2:c.-377C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322004.2:c.-242-1889C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322008.2:c.-52-1889C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322010.2:c.-242-1889C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000535.7:c.108C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322006.2:c.108C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.108C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.195C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001178287Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Oct 21, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001355292Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Apr 9, 2020) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods.

Arora S, Huwe PJ, Sikder R, Shah M, Browne AJ, Lesh R, Nicolas E, Deshpande S, Hall MJ, Dunbrack RL Jr, Golemis EA.

Cancer Biol Ther. 2017 Jul 3;18(7):519-533. doi: 10.1080/15384047.2017.1326439. Epub 2017 May 11.

PubMed [citation]
PMID:
28494185
PMCID:
PMC5639829

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV001178287.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The p.S36R variant (also known as c.108C>A), located in coding exon 2 of the PMS2 gene, results from a C to A substitution at nucleotide position 108. The serine at codon 36 is replaced by arginine, an amino acid with dissimilar properties. A functional study demonstrated that this alteration was expressed at a level similar to that of the wild type, with proficient mRNA and protein expression and viability in response to DNA-damaging agents (Arora S et al. Cancer Biol Ther, 2017 Jul;18:519-533). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV001355292.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This missense variant replaces serine with arginine at codon 36 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). A functional study has shown that this variant does not impact protein expression or cell viability in the presence of DNA-damaging agents (PMID: 28494185). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/245788 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024