NM_000059.4(BRCA2):c.280C>T (p.Pro94Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: May 1, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000589736.21

Allele description [Variation Report for NM_000059.4(BRCA2):c.280C>T (p.Pro94Ser)]

NM_000059.4(BRCA2):c.280C>T (p.Pro94Ser)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.280C>T (p.Pro94Ser)

HGVS:

NC_000013.11:g.32319289C>T
NG_012772.3:g.8810C>T
NG_017006.2:g.1075G>A
NM_000059.4:c.280C>TMANE SELECT
NP_000050.2:p.Pro94Ser
NP_000050.3:p.Pro94Ser
LRG_293t1:c.280C>T
LRG_293:g.8810C>T
LRG_293p1:p.Pro94Ser
NC_000013.10:g.32893426C>T
NM_000059.3:c.280C>T
U43746.1:n.508C>T
p.P94S

Nucleotide change:

508C>T

Protein change:

P94S

Links:

dbSNP: rs80358531

NCBI 1000 Genomes Browser:

rs80358531

Molecular consequence:

NM_000059.4:c.280C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Chromosome neighbors for GEO Profiles (Select 76502897) (17)
GEO Profiles
MBD6 methyl-CpG binding domain protein 6 [Homo sapiens]
MBD6 methyl-CpG binding domain protein 6 [Homo sapiens]
Gene ID:114785

Gene
Gene Links for GEO Profiles (Select 76521187) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000228767	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Sep 11, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000296711	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (May 1, 2023)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 33471991, 29928469, 32123317, 21120943, 19471317, 32641407, 29659569, 25348012, 26467025, 26295337
SCV000321446	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Dec 14, 2020)	germline	clinical testing	Citation Link,
SCV000591672	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

High frequency of pathogenic non-founder germline mutations in BRCA1 and BRCA2 in families with breast and ovarian cancer in a founder population.

Maksimenko J, Irmejs A, Trofimovičs G, Bērziņa D, Skuja E, Purkalne G, Miklaševičs E, Gardovskis J.

Hered Cancer Clin Pract. 2018;16:12. doi: 10.1186/s13053-018-0094-0.

PubMed [citation]

PMID:: 29928469
PMCID:: PMC5989401

See all PubMed Citations (10)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000228767.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000296711.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

In the published literature, the variant has been reported individuals with hereditary breast and ovarian cancer (PMID: 29928469 (2018) and 21120943 (2011)). Published studies indicate that this variant does not alter splicing (PMID: 32641407 (2020), 32123317 (2020)) and does not demonstrate allelic imbalance (PMID: 19471317 (2009)). The frequency of this variant in the general population, 0.00014 (5/34570 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000321446.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21120943, 19471317, 25348012, 29659569, 29928469, 32641407, 32123317)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591672.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

The p.Pro94Ser variant was identified by Caux-Moncoutier (2009) in a hereditary breast/ovarian cancer (HBOC) patient. The authors of this study used an allelic imbalance assay to assess the putative impact of variants on splicing; no allelic imbalance was found for the variant, suggesting that it does not impact splicing. The variant was also identified in dbSNP (ID: rs80358531) â€šÃ„ÃºWith non-pathogenic alleleâ€šÃ„Ã¹, and three times in UMD as an unclassified variant. The p.Pro94 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Pro94Ser variant may impact the protein. 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. This variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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