rs431825362

Variant names:

• chr13-32363187-C-A
• rs431825362
• NM_000059.4:c.7985C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32363187-C-A
• chr13-32363187-C-G
• chr13-32363187-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000059.4(BRCA2):​c.7985C>A​(p.Thr2662Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000185 in 1,460,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2662M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 4.75
• Publications: 18 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 27 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.23026547).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.7985C>A	p.Thr2662Lys	missense	Exon 18 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.7985C>A	p.Thr2662Lys	missense	Exon 18 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.7985C>A	p.Thr2662Lys	missense	Exon 18 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.7985C>A	p.Thr2662Lys	missense	Exon 18 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.7985C>A	p.Thr2662Lys	missense	Exon 18 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.7616C>A	p.Thr2539Lys	missense	Exon 18 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250098 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460966 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726828

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111564

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:5

Mar 21, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 19, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Apr 02, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with lysine at codon 2662 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. An RNA study has shown that the variant results in exon 18 skipping (PMID: 26845104). However, the impact on RNA splicing may be partial and the clinical relevance of this observation is not known. This variant has been reported in individuals affected with ovarian cancer (PMID: 22711857, 23633455) and colon cancer (PMID: 26845104), and a multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1022 and 0.566, respectively (PMID: 31131967). This variant has also been identified in 1/250098 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Jan 21, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Nov 27, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Dec 17, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with lysine at codon 2662 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing (PMID: 30661751, 35449021). An RNA study has shown that the variant results in exon 18 skipping (PMID: 26845104). However, the impact on RNA splicing may be partial and the clinical relevance of this observation is not known. This variant has been reported in individuals affected with ovarian cancer (PMID: 22711857, 23633455) and colon cancer (PMID: 26845104). Multifactorial analyses have reported likelihood ratios (LR) reaching a combined LR = 1.2950345601875 based on personal and family history of three carriers and co-occurrence with a pathogenic variant (PMID: 31131967, 31853058). This variant has also been identified in 1/250098 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

May 01, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided Uncertain:2

May 15, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA2 c.7985C>A (p.Thr2662Lys) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing sites. However, ESE finder predicts that this variant may affect multiple ESE binding sites. This prediction was confirmed by RT-PCR in patient's RNA showing skipping of exon 18 (Shirts_2015), which is predicted to lead to a frameshift change. This variant has been reported in one patient with ovarian cancer and one patient with colon cancer, without strong evidence for causality. This variant is absent in 118364 control chromosomes (ExAC). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance except one clinical diagnostic laboratory classified this variant as pathogenic (University of Washington, Shirts_2015). Taken together, this variant is classified as a "Variant of Uncertain Significance - possibly pathogenic, until additional clinical data becomes available.

Apr 15, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA2 c.7985C>A at the cDNA level, p.Thr2662Lys (T2662K) at the protein level, and results in the change of a Threonine to a Lysine (ACG>AAG). Using alternate nomenclature, this variant would be defined as BRCA2 8213C>A. This variant has been identified in at least one individual with epithelial ovarian cancer and at least one individual with colon cancer with a family history of pancreatic and breast cancer (Alsop 2012, Shirts 2016). Shirts et al (2016) performed RT-PCR on RNA from an affected individual and reported that this variant created an alternate transcript that skipped exon 18. However, this alternate transcript has been seen in controls and therefore, the significance of this finding is unknown (Tesoriero 2005, Walker 2010). BRCA2 Thr2662Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Thr2662Lys occurs at a position that is not conserved and is located in the DNA binding and SHFM1 binding domain (Marston 1999, Yang 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Thr2662Lys is pathogenic or benign. We consider this to be a variant of uncertain significance.

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1

Dec 11, 2020

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is predicted to alter exonic splice enhancers. RT-PCR of RNA showed exon 18 skipping. Evidence from other variants that show partial skipping suggest a variable phenotype associated with exon skipping. Additional data is needed to determine the level of risk associated with this variant.

Malignant tumor of breast Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Thr2662Lys variant was identified in 1 of 2924 proband chromosomes (frequency: 0.0003) from individuals or families with hereditary cancer (Shirts 2016). The variant was also identified in dbSNP (ID: rs431825362 as With Pathogenic, Uncertain significance allele) and ClinVar (7x as a variant of uncertain significance, 1x as likely pathogenic, and 1x as pathogenic). The variant was not identified in Cosmic, MutDB, LOVD 3.0, ARUP Laboratories, or Zhejiang University Database. The variant was identified in control databases in 1 of 244984 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish population in 1 of 110928 chromosomes (freq: 0.000009) and was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. This variant has been shown to alter splicing of the BRCA2 transcript, resulting in the skipping of exon 18 (Shirts 2016); however, the biological significance of this splicing alteration is unclear. The p.Thr2662 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of this amino acid substitution to the protein; this information is not reliably predictive of 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 uncertain significance.

Hereditary breast ovarian cancer syndrome Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.77	T
PhyloP100		4.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Vest4		0.27
MutPred		0.58		Loss of phosphorylation at T2662 (P = 0.0156)
MVP		0.87
MPC		0.021
ClinPred		0.47	T
GERP RS		4.9
gMVP		0.37
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs431825362; hg19: chr13-32937324;