13-32333109-C-T

Position:

• chr13-32333109-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.1631C>T​(p.Thr544Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. T544P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 0.761

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24070257).
• BP6: Variant 13-32333109-C-T is Benign according to our data. Variant chr13-32333109-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51160.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1631C>T	p.Thr544Ile	missense_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1631C>T	p.Thr544Ile	missense_variant	10/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.1262C>T	p.Thr421Ile	missense_variant	10/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1631C>T		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251030 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135662

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461668 Hom.: 0 Cov.: 35 AF XY: 0.0000303 AC XY: 22 AN XY: 727104

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 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. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Apr 12, 1999	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 25, 2016	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	This variant is associated with the following publications: (PMID: 22711857, 26580448, 25356972, 24817641, 25348012, 21952622) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 09, 2021	The BRCA2 c.1631C>T; p.Thr544Ile variant (rs80358448) is reported in the literature in an individual affected with acute lymphocytic leukemia, in an individual with prostate cancer and in an individual with family history of cancer, but the variant was not determined to be causative (Kote-Jarai 2011, Zhang 2015, Zhen 2015). This variant is also reported in an individual with ovarian cancer who also carried another pathogenic variant (Alsop 2012). The variant is reported with discrepant classifications in the ClinVar database (Variation ID: 51160) and is listed in the general population with an overall allele frequency of 0.002% (6/282,426 alleles) in the Genome Aggregation Database. The threonine at codon 544 is weakly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.188). Due to limited information, the clinical significance of the p.Thr544Ile variant is uncertain at this time. References: Alsop K et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012 Jul 20;30(21):2654-63. PMID: 22711857. Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011 Oct 11;105(8):1230-4. PMID: 21952622. Zhang J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015 Dec 10;373(24):2336-2346. PMID: 26580448. Zhen DB et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015 Jul;17(7):569-77. PMID: 25356972. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 09, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 29, 2024

Variant summary: BRCA2 c.1631C>T (p.Thr544Ile) 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 2e-05 in 251030 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, this variant has also been reported in 2/7325 European American women who were older than age 70, and cancer free (in the FLOSSIES database). c.1631C>T has been reported in the literature in sequencing studies with variable cohort characteristics, e.g. nonmucinous ovarian carcinoma (Alsop_2012), prostate cancer (Kote-Jarai_2011), positive family history of pancreatic cancer (Zhen_2015), exome and genome sequencing studies (Zhang_2015). In a large case-control study evaluating breast cancer (BrC) cases and controls in the Breast Cancer Association Consortium (BCAC) the variant was reported in 2/60466 cases and 1/53461 controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.3756_3759delGTCT (p.Ser1253fs*10) in the UMD database; BRCA1 exon 12 dup in the BIC database; and a non-specified pathogenic variant in the BRCA1/2 gene, Alsop_2012), 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: 22711857, 34326862, 33471991, 24817641, 21952622, 31131967, 26580448, 25356972).ClinVar contains an entry for this variant (Variation ID: 51160). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.2
DANN	Benign	0.79
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.11	N
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.94	N;N
REVEL	Benign	0.19
Sift	Benign	0.17	T;T
Sift4G	Benign	0.14	T;T
Vest4		0.38
MVP		0.84
MPC		0.021
ClinPred		0.047	T
GERP RS		3.7
gMVP		0.11

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: rs80358448; hg19: chr13-32907246; COSMIC: COSV99061619;