13-32398624-A-G

Position:

• chr13-32398624-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000059.4(BRCA2):​c.10111A>G​(p.Thr3371Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3 B:13
• Conservation: PhyloP100: 0.785

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.101763666).
• BP6: Variant 13-32398624-A-G is Benign according to our data. Variant chr13-32398624-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 37720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.10111A>G	p.Thr3371Ala	missense_variant	27/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.10111A>G	p.Thr3371Ala	missense_variant	27/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9742A>G	p.Thr3248Ala	missense_variant	27/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*2169A>G		non_coding_transcript_exon_variant	26/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*2169A>G		3_prime_UTR_variant	26/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 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: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251284 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000384

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2020	This variant is associated with the following publications: (PMID: 22703879, 27376475, 25682074, 20104584, 26580448, 26933808) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 24, 2018	The BRCA2 c.10111A>G; p.Thr3371Ala variant (rs80358393) has been described in individuals affected with breast cancer who also harbor a known pathogenic BRCA1 variant (see link to BIC database). This variant has also been observed in individuals with no personal or family history of cancer (Johnston 2012). It is reported in ClinVar (Variation ID: 37720) and observed in the general population at an overall frequency of 0.0007% (2/277018 alleles) in the Genome Aggregation Database. The threonine at codon 3371 is moderately conserved but computational algorithms (PolyPhen-2, SIFT) predict this variant to be tolerated. Based on available information, this variant is considered likely benign. References: BIC database: https://research.nhgri.nih.gov/bic/ Johnston J et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012 Jul 13;91(1):97-108. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 10, 2020	- -

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

Likely benign, criteria provided, single submitter	literature only	Counsyl	Feb 05, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jun 12, 2000	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 01, 2012	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 10, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 07, 2024	Variant summary: BRCA2 c.10111A>G (p.Thr3371Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251284 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10111A>G has been reported in the literature in individuals affected with or undergoing testing for breast and/or other types of cancer (example, Borg_2010, Capanu_2011, Schenkel_2016, Wong-Brown_2015, Xiu_2016, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant have been reported (BRCA1 c.5335delC, p.Gln1779fsX14; BRCA1 c.4612C>T, p.Gln1538X; BRCA1 c.3778_3779insA, p.Leu1260fs), providing supporting evidence for a benign role. 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: 22703879, 20104584, 21520273, 24817641, 25682074, 27376475, 26933808, 26580448, 33471991). ClinVar contains an entry for this variant (Variation ID: 37720). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2022	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Thr3371Ala variant was identified in 3 of 4206 proband chromosomes (frequency: 0.001) from individuals or families with contralateral and unilateral breast cancer (Borg 2010). The variant was also previously identified by our laboratory in 1 individual with breast cancer. The p.Thr3371Ala variant was identified in the dbSNP with “Other” allele. This variant was identified in ClinVar database as likely benign by Ambry Genetics, GeneDX and Counsyl; as benign by Sharing Clinical Reports Project derived by Myriad Reports; as uncertain significance by Invitae, BIC and Biesecker laboratory ClinSeq Project NHGRI. The p.Thr3371Ala variant was identified in BIC 3x with unknown clinical importance; in BRCA Share UMD 1x and classified as unknown. The variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (released March 14, 2016), GeneInsight COGR, Clinvitae, COSMIC, MutDB, LOVD Fanconi’s Anemia Mutation and ARUP Laboratories Databases. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The p.Thr3371 residue is conserved in mammals and not in lower organism and the variant amino acid Alanine is present in chicken, increasing the likelihood that this variant does not have clinical significance. 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 11, 2021

- -

BRCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.099	N
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.093
Sift	Benign	0.18	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.14
MutPred		0.069		Loss of phosphorylation at T3371 (P = 0.0832);Loss of phosphorylation at T3371 (P = 0.0832);
MVP		0.79
MPC		0.13
ClinPred		0.51	D
GERP RS		4.5
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358393; hg19: chr13-32972761;