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NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp) AND Hereditary breast ovarian cancer syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 19, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV004764762.2

Allele description [Variation Report for NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp)]

NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp)

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.2249G>A (p.Gly750Asp)
HGVS:
  • NC_000007.14:g.5978622C>T
  • NG_008466.1:g.35485G>A
  • NM_000535.7:c.2249G>AMANE SELECT
  • NM_001322003.2:c.1844G>A
  • NM_001322004.2:c.1844G>A
  • NM_001322005.2:c.1844G>A
  • NM_001322006.2:c.2093G>A
  • NM_001322007.2:c.1931G>A
  • NM_001322008.2:c.1931G>A
  • NM_001322009.2:c.1844G>A
  • NM_001322010.2:c.1688G>A
  • NM_001322011.2:c.1316G>A
  • NM_001322012.2:c.1316G>A
  • NM_001322013.2:c.1676G>A
  • NM_001322014.2:c.2249G>A
  • NM_001322015.2:c.1940G>A
  • NP_000526.2:p.Gly750Asp
  • NP_001308932.1:p.Gly615Asp
  • NP_001308933.1:p.Gly615Asp
  • NP_001308934.1:p.Gly615Asp
  • NP_001308935.1:p.Gly698Asp
  • NP_001308936.1:p.Gly644Asp
  • NP_001308937.1:p.Gly644Asp
  • NP_001308938.1:p.Gly615Asp
  • NP_001308939.1:p.Gly563Asp
  • NP_001308940.1:p.Gly439Asp
  • NP_001308941.1:p.Gly439Asp
  • NP_001308942.1:p.Gly559Asp
  • NP_001308943.1:p.Gly750Asp
  • NP_001308944.1:p.Gly647Asp
  • LRG_161t1:c.2249G>A
  • LRG_161:g.35485G>A
  • NC_000007.13:g.6018253C>T
  • NM_000535.5:c.2249G>A
  • NM_000535.6:c.2249G>A
  • NR_136154.1:n.2336G>A
  • p.G750D
Protein change:
G439D
Links:
dbSNP: rs587779337
NCBI 1000 Genomes Browser:
rs587779337
Molecular consequence:
  • NM_000535.7:c.2249G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322003.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322004.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322005.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322006.2:c.2093G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322007.2:c.1931G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322008.2:c.1931G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322009.2:c.1844G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322010.2:c.1688G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322011.2:c.1316G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322012.2:c.1316G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322013.2:c.1676G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.2249G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322015.2:c.1940G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.2336G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Hereditary breast ovarian cancer syndrome
Synonyms:
Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005374647German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
criteria provided, single submitter

(ClinGen PMS2 V1.0.0)		Likely pathogenic
(Nov 19, 2024) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedcuration

Details of each submission

From German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, SCV005374647.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

According to the ClinGen InSiGHT ACMG PMS2 v1.0.0 criteria we chose these criteria: PS3 (supporting pathogenic): Drost et al. 2013, PMID: 24027009, PM3 (medium pathogenic): This variant has been reported to occur with other PMS2 pathogenic variants in individuals with suspected mismatch repair deficiency syndrome and/or colorectal cancer (Senter et al. 2008. PubMed ID: 18602922; Lavoine et al. 2015. PubMed ID: 26318770; Table S1, Goodenberger et al. 2016. PubMed ID: 25856668). In at least one case, the variants were determined to be on opposite alleles (Senter et al. 2008. PubMed ID: 18602922). However, in at least two individuals with colorectal cancer there was a second pathogenic PMS2 variant present; however, phase was not determined (Supplemental Data, Bodo et al. 2015. PubMed ID: 26116798; Table S1, Goodenberger et al. 2016. PubMed ID: 25856668). Strength?, PP3 (medium pathogenic): MAPP/PP2 Prior P score: 0.9603 , PP4 (medium pathogenic): Bodo (2015, PMID: 26116798): ColorectalCa --> MSI & PMS2 lost in Normal and Tumor tissue Senter (2009, PMID: 18602922): IHC results from these probands’ tumor analyses [including c.2249G>A] demonstrated loss of PMS2 expression in their tumors Goodenberger (2016, PMID: 25856668): MSI-H, IHC: PMS2 loss Shuen (2019, PMID: 30608896): PMS2 loss & MMR activity: 8.27

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

Last Updated: Nov 24, 2024