rs80358402

Variant names:

• chr13-32398735-A-T
• rs80358402
• NM_000059.4:c.10222A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_000059.4(BRCA2):​c.10222A>T​(p.Lys3408*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K3408K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.805
• Publications: 7 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 1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00341 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 13-32398735-A-T is Benign according to our data. Variant chr13-32398735-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 51056.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.10222A>T	p.Lys3408*	stop_gained	Exon 27 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.10222A>T	p.Lys3408*	stop_gained	Exon 27 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9853A>T	p.Lys3285*	stop_gained	Exon 27 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*2280A>T		non_coding_transcript_exon_variant	Exon 26 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*2280A>T		3_prime_UTR_variant	Exon 26 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251000 AF XY: 0.00000737

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44690

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

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

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111966

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:2

Apr 05, 2017

Counsyl

Significance: Likely benign

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. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Lys3408X variant was not identified in the literature but was identified in the BIC database (1X with no clinical importance), dbSNP (ID: rs80358402), and in the ClinVar database (classified as likely benign by GeneDx and Ambry Genetics; classified as benign by BIC; classification not provided by Invitae). The variant was listed in the Exome Aggregation Consortium (ExAC) database in 1 of 65858 chromosomes (frequency: 0.00002) from a population of European (Non-Finnish) individuals; however, this single observation and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant results in termination of translation at amino acid position 3408 and the loss of the terminal 9 amino acids of the expressed BRCA2 protein. Borg (2010) identified three variants in the BRCA2 gene near the 3’-end which were predicted to result in protein truncation (c.9976A>T (BIC: K3326X), c.10095delCins11 (BIC: 10323delCins11), c.10150C>T (BIC: R3384X), but were “ruled as exceptions that could not be classified because of their location near the 3’-end and possibly dispensable part of the gene”. The p.Lys3408X variant is located even farther downstream than these variants (i.e. closer to the 3’- end of the gene). Stop codon or nonsense mutations in the last exon of a gene may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. Segregation and/or functional studies are recommended to further elucidate the pathogenicity of this variant. 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. -

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Breast Cancer Information Core (BIC) (BRCA2)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Mar 12, 2019

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. -

Feb 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_NA, PM5_NA c.10222A>T, located in exon 27 of the BRCA2 gene, is a nonsense variant expected to result in premature protein truncation, p.(Lys3408*). This alteration, however, is located downstream position p.Glu3309 (PVS1_NA, PM5_NA). The variant was found in 2/267916 alleles, at a frequency of 0.0007% in the gnomAD v2.1.1 database, non-cancer dataset. No effect is predicted on splicing by SpliceAI. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. This variant has been reported in ClinVar database (2x benign, 6x likely benign, 1x uncertain significance) and in BRCA Exchange database as not yet reviewed, but it has not been reported in LOVD. Based on currently available information, the variant c.10222A>T should be considered an uncertain significance variant. -

not provided Benign:2

Jan 17, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

not specified Benign:1

Jan 30, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.10222A>T (p.Lys3408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein but not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 1.7e-05 in 1613940 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (1.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.10222A>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome without strong evidence for or against pathogenicity (example: Pirim_2020, Darst_2021, Bisgin_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32599251, 32853339, 35753294). ClinVar contains an entry for this variant (Variation ID: 51056). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Benign	0.87
Eigen	Benign	-0.64
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.045	N
PhyloP100		-0.81
Vest4		0.49
GERP RS		-9.1
Mutation Taster		=132/68	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80358402; hg19: chr13-32972872;