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

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 31, 2024
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:: RCV000254706.18

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]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000694632	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 24, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19471317, 21120943, 29659569, 29928469, 35264596, 35979650 Citation Link,
SCV002066668	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005090007	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000694632

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Aug 24, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002066668

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 23, 2020)

germline

clinical testing

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

SCV005090007

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jul 31, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nothing to display

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694632.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: BRCA2 c.280C>T (p.Pro94Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.280C>T has been reported in the literature in individuals affected with breast or ovarian cancer and HBOC (example, Caux-Moncoutier_2009, Ortiz_2016, Maksimenko_2018, Guindalini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed (BRCA1 c.5266dup, p.Gln1756fsX74 in UMD database), providing supporting evidence for a benign role. This variant had no effect in a study assessing allelic imbalance as an indirect measure of the impact of out-of-frame defects leading to reductions in the levels of mutant mRNA cleared through NMD (example, Caux-Moncoutier 2009). Consistent with this result, a second study has shown variant has no effect on splicing and classified the variant as benign (Thomassen_ 2022). This supports the notion that this variant has no effect on splicing. The following publications have been ascertained in the context of this evaluation (PMID: 19471317, 21120943, 29928469, 29659569, 35979650, 35264596). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) and VUS (n=7). Based on the evidence outlined above, the variant was classified as likely benign.

#	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		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002066668.1

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

Description

DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.280C>T, in exon 3 that results in an amino acid change, p.Pro94Ser. This sequence change does not appear to have been previously described in patients with BRCA2-related disorders and has been described in the gnomAD database with a frequency of 0.014% in the Latino sub-population (dbSNP rs80358531). The p.Pro94Ser change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro94Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro94Ser change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV005090007.1

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

Last Updated: Oct 13, 2024

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