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NM_000535.7(PMS2):c.1012C>G (p.Pro338Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Sep 29, 2021
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:
RCV000219397.7

Allele description [Variation Report for NM_000535.7(PMS2):c.1012C>G (p.Pro338Ala)]

NM_000535.7(PMS2):c.1012C>G (p.Pro338Ala)

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.1012C>G (p.Pro338Ala)
HGVS:
  • NC_000007.14:g.5989932G>C
  • NG_008466.1:g.24175C>G
  • NM_000535.7:c.1012C>GMANE SELECT
  • NM_001322003.2:c.607C>G
  • NM_001322004.2:c.607C>G
  • NM_001322005.2:c.607C>G
  • NM_001322006.2:c.988+2041C>G
  • NM_001322007.2:c.694C>G
  • NM_001322008.2:c.694C>G
  • NM_001322009.2:c.607C>G
  • NM_001322010.2:c.583+2041C>G
  • NM_001322011.2:c.79C>G
  • NM_001322012.2:c.79C>G
  • NM_001322013.2:c.439C>G
  • NM_001322014.2:c.1012C>G
  • NM_001322015.2:c.703C>G
  • NP_000526.2:p.Pro338Ala
  • NP_001308932.1:p.Pro203Ala
  • NP_001308933.1:p.Pro203Ala
  • NP_001308934.1:p.Pro203Ala
  • NP_001308936.1:p.Pro232Ala
  • NP_001308937.1:p.Pro232Ala
  • NP_001308938.1:p.Pro203Ala
  • NP_001308940.1:p.Pro27Ala
  • NP_001308941.1:p.Pro27Ala
  • NP_001308942.1:p.Pro147Ala
  • NP_001308943.1:p.Pro338Ala
  • NP_001308944.1:p.Pro235Ala
  • LRG_161t1:c.1012C>G
  • LRG_161:g.24175C>G
  • NC_000007.13:g.6029563G>C
  • NM_000535.5:c.1012C>G
  • NM_000535.6:c.1012C>G
  • NR_136154.1:n.1099C>G
Protein change:
P147A
Links:
dbSNP: rs876660508
NCBI 1000 Genomes Browser:
rs876660508
Molecular consequence:
  • NM_001322006.2:c.988+2041C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001322010.2:c.583+2041C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000535.7:c.1012C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322003.2:c.607C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322004.2:c.607C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322005.2:c.607C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322007.2:c.694C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322008.2:c.694C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322009.2:c.607C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322011.2:c.79C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322012.2:c.79C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322013.2:c.439C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.1012C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322015.2:c.703C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.1099C>G - 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
SCV000277996Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Sep 29, 2021) 		germlineclinical testing

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

Citation Link,

SCV000904820Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jan 6, 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

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S.

J Clin Oncol. 2017 Apr 1;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30.

PubMed [citation]
PMID:
28135145
PMCID:
PMC5455355

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, SCV000277996.7

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

Description

The p.P338A variant (also known as c.1012C>G), located in coding exon 10 of the PMS2 gene, results from a C to G substitution at nucleotide position 1012. The proline at codon 338 is replaced by alanine, an amino acid with highly similar properties. This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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, SCV000904820.3

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

Description

This missense variant replaces proline with alanine at codon 338 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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: Jun 9, 2024