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NM_000535.7(PMS2):c.944G>A (p.Arg315Gln) AND not provided

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
May 3, 2024
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:
RCV000679365.11

Allele description [Variation Report for NM_000535.7(PMS2):c.944G>A (p.Arg315Gln)]

NM_000535.7(PMS2):c.944G>A (p.Arg315Gln)

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.944G>A (p.Arg315Gln)
HGVS:
  • NC_000007.14:g.5992017C>T
  • NG_008466.1:g.22090G>A
  • NM_000535.7:c.944G>AMANE SELECT
  • NM_001322003.2:c.539G>A
  • NM_001322004.2:c.539G>A
  • NM_001322005.2:c.539G>A
  • NM_001322006.2:c.944G>A
  • NM_001322007.2:c.626G>A
  • NM_001322008.2:c.626G>A
  • NM_001322009.2:c.539G>A
  • NM_001322010.2:c.539G>A
  • NM_001322011.2:c.11G>A
  • NM_001322012.2:c.11G>A
  • NM_001322013.2:c.371G>A
  • NM_001322014.2:c.944G>A
  • NM_001322015.2:c.635G>A
  • NP_000526.2:p.Arg315Gln
  • NP_001308932.1:p.Arg180Gln
  • NP_001308933.1:p.Arg180Gln
  • NP_001308934.1:p.Arg180Gln
  • NP_001308935.1:p.Arg315Gln
  • NP_001308936.1:p.Arg209Gln
  • NP_001308937.1:p.Arg209Gln
  • NP_001308938.1:p.Arg180Gln
  • NP_001308939.1:p.Arg180Gln
  • NP_001308940.1:p.Arg4Gln
  • NP_001308941.1:p.Arg4Gln
  • NP_001308942.1:p.Arg124Gln
  • NP_001308943.1:p.Arg315Gln
  • NP_001308944.1:p.Arg212Gln
  • LRG_161t1:c.944G>A
  • LRG_161:g.22090G>A
  • NC_000007.13:g.6031648C>T
  • NM_000535.5:c.944G>A
  • NM_000535.6:c.944G>A
  • NR_136154.1:n.1031G>A
  • p.R315Q
Protein change:
R124Q
Links:
dbSNP: rs116314131
NCBI 1000 Genomes Browser:
rs116314131
Molecular consequence:
  • NM_000535.7:c.944G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322003.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322004.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322005.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322006.2:c.944G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322007.2:c.626G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322008.2:c.626G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322009.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322010.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322011.2:c.11G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322012.2:c.11G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322013.2:c.371G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.944G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322015.2:c.635G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.1031G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000279135GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Uncertain significance
(May 3, 2024) 		germlineclinical testing

Citation Link,

SCV001551954Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

SCV004219037Quest Diagnostics Nichols Institute San Juan Capistrano
criteria provided, single submitter

(Quest Diagnostics criteria)		Uncertain significance
(Aug 25, 2023) 		unknownclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.

Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.

PubMed [citation]
PMID:
26845104

Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.

Nikitin AG, Chudakova DA, Enikeev RF, Sakaeva D, Druzhkov M, Shigapova LH, Brovkina OI, Shagimardanova EI, Gusev OA, Gordiev MG.

Front Oncol. 2020;10:666. doi: 10.3389/fonc.2020.00666.

PubMed [citation]
PMID:
32547938
PMCID:
PMC7273971
See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000279135.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with breast cancer, sarcoma, or a family history of ovarian cancer, but also observed in unaffected controls (PMID: 25503501, 26845104, 27498913, 32547938, 32980694, 33471991); This variant is associated with the following publications: (PMID: 25503501, 26845104, 27498913, 32547938, 32980694, 33471991, 11574484, 36243179, 37306523)

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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551954.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The PMS2 p.Arg315Gln variant was identified in 2 of 3480 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer (Maxwell 2014, Shirts 2016). The variant was also identified in dbSNP (ID: rs116314131) as “With Uncertain significance allele”, and in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Coulsyl and two clinical laboratories). The variant was not identified in COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 6 of 277006 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24006 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), and European in 4 of 126670 chromosomes (freq: 0.00003); it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg315 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219037.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 32547938 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)), including one affected individual who co-carried a pathogenic CHEK2 variant (PMID: 25503501 (2015)). This variant has also been observed in an individual with a family history of ovarian cancer (PMID: 26845104 (2016)), and in several unaffected control individuals (PMIDs: 36243179 (2022), 33471991 (2021), 32980694 (2020)). The frequency of this variant in the general population, 0.000035 (4/113696 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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

Last Updated: Sep 29, 2024