NM_000059.4(BRCA2):c.1889C>T (p.Thr630Ile) AND not provided

Germline classification:: Benign/Likely benign (5 submissions)
Last evaluated:: Jun 1, 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:: RCV000034433.42

Allele description [Variation Report for NM_000059.4(BRCA2):c.1889C>T (p.Thr630Ile)]

NM_000059.4(BRCA2):c.1889C>T (p.Thr630Ile)

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.1889C>T (p.Thr630Ile)

Other names:

p.T630I:ACA>ATA; 2117C>T

HGVS:

NC_000013.11:g.32333367C>T
NG_012772.3:g.22888C>T
NM_000059.4:c.1889C>TMANE SELECT
NP_000050.2:p.Thr630Ile
NP_000050.3:p.Thr630Ile
LRG_293t1:c.1889C>T
LRG_293:g.22888C>T
LRG_293p1:p.Thr630Ile
NC_000013.10:g.32907504C>T
NM_000059.3:c.1889C>T
U43746.1:n.2117C>T
p.T630I

Protein change:

T630I

Links:

dbSNP: rs80358479

NCBI 1000 Genomes Browser:

rs80358479

Molecular consequence:

NM_000059.4:c.1889C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000043200	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	no assertion criteria provided	variant of unknown significance (Jul 13, 2012)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000602820	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely benign (Mar 21, 2023)	germline	clinical testing	Citation Link,
SCV000694581	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Aug 22, 2016)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12161607, 23231788, 20960228, 17250666, 21990134, 21520273, 18403564, 17924331, 22703879, 18284688, 24323938, 20104584 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000778649	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Likely benign (Feb 28, 2018)	unknown	clinical testing
SCV001961398	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Jun 1, 2024)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	1	not provided	not provided	572	not provided	research
not provided	germline	yes	11	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families.

Kauff ND, Perez-Segura P, Robson ME, Scheuer L, Siegel B, Schluger A, Rapaport B, Frank TS, Nafa K, Ellis NA, Parmigiani G, Offit K.

J Med Genet. 2002 Aug;39(8):611-4. No abstract available.

PubMed [citation]

PMID:: 12161607
PMCID:: PMC1735198

Variants of uncertain significance in BRCA1 and BRCA2 assessment of in silico analysis and a proposal for communication in genetic counselling.

Moghadasi S, Hofland N, Wouts JN, Hogervorst FB, Wijnen JT, Vreeswijk MP, van Asperen CJ.

J Med Genet. 2013 Feb;50(2):74-9. doi: 10.1136/jmedgenet-2012-100961. Epub 2012 Dec 11.

PubMed [citation]

PMID:: 23231788

See all PubMed Citations (12)

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000043200.1

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

Description

The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See PubMed ID:22703879 for details.

Description

Converted during submission to Uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	572	not provided	discovery		1	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000602820.3

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694581.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

Variant summary: The BRCA2 c.1889C>T (p.Thr630Ile) variant causes a missense change involving a non-conserved nucleotide with 3/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 21/116384 (1/5543), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals, in particular, reputable databases have cited the variant to co-occur with multiple pathogenic BRCA2 variants, 1 - c.6468_6469delTC (p.Gln2157IlefsX18), 2 - c.4829_4830delTG (p.Val1610fs), 1 - c.276dupA (p.Gln92fs), and BRCA1 variants, 1 - c.4936delG (Val1646fs), 1 - c.3700_3704delGTAAA (p.Val1234fs), c.5263dupC (p.Ser1755fs). In additional, multiple reputable databases/clinical laboratories and publications cite the variant as "likely benign/benign." Therefore, the variant of interest has been classified as 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 Mayo Clinic Laboratories, Mayo Clinic, SCV000778649.1

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

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001961398.21

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	not provided

Description

BRCA2: BP4

#	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		11	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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