17-43063888-A-G

Position:

• chr17-43063888-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_007294.4(BRCA1):​c.5138T>C​(p.Val1713Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. V1713E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:4 O:1
• Conservation: PhyloP100: 5.76

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063887-TA-CC is described in ClinVar as [Pathogenic]. Clinvar id is 1745580.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 17-43063888-A-G is Pathogenic according to our data. Variant chr17-43063888-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55412.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5138T>C	p.Val1713Ala	missense_variant	17/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5138T>C	p.Val1713Ala	missense_variant	17/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251322 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 18, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 21, 2018	The BRCA1 c.5138T>C; p.Val1713Ala variant (rs80357132) is described in the literature in a proband with breast and ovarian cancer, as well as a strong family history of breast and ovarian cancer (Struewing 1995). Functional analyses suggest the variant causes altered substrate binding and specificity as well as altered transcriptional activity (Carvalho 2007, Lee 2010). This variant is reported in ClinVar (Variation ID: 55412). It is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 1713 is highly conserved and computational analyses (SIFT, PolyPhen2) predict that this variant may be deleterious. However, due to limited information, the clinical significance of the p.Val1713Ala variant is uncertain at this time. REFERENCES Carvalho MA et al. Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Res. 2007 Feb 15;67(4):1494-501. Lee MS et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010 Jun 15;70(12):4880-90. Struewing JP et al. Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer. Am J Hum Genet. 1995 Jul;57(1):1-7. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 10, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 10, 2002	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2023	Variant summary: BRCA1 c.5138T>C (p.Val1713Ala) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251322 control chromosomes. c.5138T>C has been reported in the literature in individuals from large families affected with Hereditary Breast and Ovarian Cancer, however without evidence of co-segregation to support causality (e.g. Struewing_1995, Humphrey_1997, Trujillano_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. For example, the variant has been reproducibly reported to reduce BRCA1 transactivation activity (Carvalho_2007, Lee_2010, Woods_2016) and phosphopeptide binding /specificity (Lee_2010). This variant has been cited as a "hypomorphic variant" in the literature (Woods_2016). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 20516115, 14534301, 9159158, 17308087, 7611277, 18992264, 24845084, 25556971, 21309043, 28781887, 30765603, 21447777). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n= 7; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 19, 2023	ClinVar contains an entry for this variant (Variation ID: 55412). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17305420, 17308087, 20516115, 21447777, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7611277, 25556971; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1713 of the BRCA1 protein (p.Val1713Ala). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2022

The p.V1713A variant (also known as c.5138T>C), located in coding exon 16 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5138. The valine at codon 1713 is replaced by alanine, an amino acid with similar properties. This alteration was seen in a proband with breast and ovarian cancer. This individual's family history was significant for breast and ovarian cancer, but co-segregation could not be established due to family members being deceased (Struewing JP et al. Am. J. Hum. Genet., 1995 Jul;57:1-7). Multiple transcriptional activation functional studies classified this variant as functionally deleterious (Findlay GM et al. Nature, 2018 10;562:217-222; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69; Woods NT et al. NPJ Genom Med, 2016 Mar). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). V1713A destabilizes the structure as much as other pathogenic variants nearby (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.0	D;N;.;D;.;.;N;D;D;N;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.81, 0.97, 0.99	.;P;.;.;.;D;.;.;.;D;.
Vest4		0.91
MVP		1.0
MPC		0.44
ClinPred		0.94	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80357132; hg19: chr17-41215905; COSMIC: COSV58797228; COSMIC: COSV58797228;