rs80359038

Positions:

• chr13-32363229-T-C

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.8027T>C​(p.Met2676Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:10
• Conservation: PhyloP100: 0.256

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=0.26375145).
• BP6: Variant 13-32363229-T-C is Benign according to our data. Variant chr13-32363229-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 38136.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.8027T>C	p.Met2676Thr	missense_variant	18/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8027T>C	p.Met2676Thr	missense_variant	18/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7658T>C	p.Met2553Thr	missense_variant	18/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*85T>C		non_coding_transcript_exon_variant	17/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*85T>C		3_prime_UTR_variant	17/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251108 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135720

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461718 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 05, 2010	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 10, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jun 12, 2000	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2019	This variant is associated with the following publications: (PMID: 21990134, 23108138, 24323938, 20104584, 18824701, 19043619, 31131967, 29394989, 29884841) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 08, 2018	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 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	Apr 28, 2016	- -

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.Met2676Thr variant was identified in 2 of 4410 proband chromosomes (frequency 0.0005) from individuals with breast cancer (Borg 2010, Spearman 2008). The variant was also identified in dbSNP (ID: rs80359038) “With unknown allele” and LOVD. The p.Met2676Thr residue is not conserved in mammals and lower organisms, and the variant amino acid Threonine (Thr) is present in chicken, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Two functional assays found the variant to be competent at homology-directed repair (Guidugli 2013, Karchin 2008), and three in silico studies predicted this variant to be likely nonpathogenic or neutral (Guidugli 2013, Karchin 2008, Lindor 2012). One histology-based predictive study was inconclusive, but the results for this variant were limited to one tumour specimen (Spearman 2008). 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 13, 2021

Variant summary: BRCA2 c.8027T>C (p.Met2676Thr) 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 1.6e-05 in 251108 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8027T>C has been reported in the recent literature to have a benign HDR (homology directed repair) activity score of 5.66 (95% CI 4.86-6.57), also citing other studies such as Ikegami_2020 reporting a fClass1 (neutral) outcome utilizing BRCA2-deficient cells and poly (ADP-ribose) polymerase (PARP) inhibitors (Olaparib, Niraparib, Rucaparib, CBDCA) and an ACMG categorization of BS3, BP4 for a final classification of likely benign (Richardson_2021). This is further supported by Lindor_2012 reporting a class 2 (neutral) outcome based on multifactorial data and the ClinGen SVI criteria that now recognize ACMG BS3 criterion as sufficient evidence for a likely benign outcome (Tavtigian_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant with a predomiant consensus supporting a as benign (n=1)/likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -

BRCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

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

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Benign	0.70
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.46	T;T
Sift4G	Benign	0.53	T;T
Vest4		0.37
MutPred		0.65		Loss of catalytic residue at M2676 (P = 5e-04);Loss of catalytic residue at M2676 (P = 5e-04);
MVP		0.81
MPC		0.024
ClinPred		0.091	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.50

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: rs80359038; hg19: chr13-32937366;