17-43057113-T-C

Variant names:

• chr17-43057113-T-C
• rs80357227
• NM_007294.4:c.5216A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5216A>G​(p.Asp1739Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,786 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1739V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2 O:1
• Conservation: PhyloP100: 4.74

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43057113-T-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 17-43057113-T-C is Pathogenic according to our data. Variant chr17-43057113-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43057113-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5216A>G	p.Asp1739Gly	missense_variant	Exon 19 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5216A>G	p.Asp1739Gly	missense_variant	Exon 19 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Uncertain:1 Other:1

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

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Nov 14, 1997

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 09, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5216A>G (p.Asp1739Gly) variant in the BRCA1 gene has been reported in multiple individuals with hereditary breast and ovarian cancer (PMID: 9333265, 12827452, 15800311, 19491284, 19949876). This variant has not been observed in the gnomAD database. Functional assays showed deleterious effect of this change (PMID: 20516115, 23867111). The Asp 1739 is a highly conserved residue, and multiple algorithms predicted this change to be deleterious. Therefore, the c.5216A>G (p.Asp1739Gly) variant in the BRCA1 gene is classified as likley pathogenic. -

Feb 25, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 16, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 9333265, 12827452, 15800311, 19491284, 19949876, 29752822, 34597585, 35534704); Published functional studies demonstrate a damaging effect: defective protein folding, compromised peptide binding activity and binding specificity, reduced transcriptional activity, impaired cisplatin sensitivity, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 20516115, 23867111, 28781887, 30209399, 30765603, 29884841, 35665744); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5335A>G; This variant is associated with the following publications: (PMID: 12827452, 20516115, 30209399, 31131967, 15004537, 28781887, 23867111, 31447099, 17305420, 15172985, 29752822, 34597585, 19491284, 30765603, 19949876, 15800311, 9333265, 29884841, 35665744, 35534704, 25348405, 32546644) -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1739G pathogenic mutation (also known as c.5216A>G), located in coding exon 18 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5216. The aspartic acid at codon 1739 is replaced by glycine, an amino acid with similar properties. This alteration has been identified in several cohorts of breast and/or ovarian cancer patients and has been observed to segregate with disease in one of these families (Shattuck-Eidens D et al. JAMA, 1997 Oct;278:1242-50; Rostagno P et al. J. Hum. Genet., 2003 Jun;48:362-6; Gómez-García EB et al. J. Clin. Oncol., 2005 Apr;23:2185-90; Haffty BG et al. Ann. Oncol., 2009 Oct;20:1653-9; van Harssel JJ et al. Fam. Cancer, 2010 Jun;9:193-201; Li JY et al. Int J Cancer, 2019 01;144:281-289). This alteration was also found to be deficient in several functional studies including a high-throughput, genome editing, haploid cell survival assay, a yeast small colony assay, binding activity and specificity assays, transcription activation assays and cisplatin sensitivity assays (Findlay GM et al. Nature, 2018 10;562:217-222; Coyne RS et al. Cancer Biol. Ther., 2004 May;3:453-7; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Bouwman P et al. Cancer Discov, 2013 Oct;3:1142-55; Woods NT et al. NPJ Genom Med, 2016 Mar;1; Bouwman P et al. Clin Cancer Res, 2020 09;26:4559-4568; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69). Several publications predict this alteration to have significant structural impact (Huyton T et al. Mutat. Res., 2000 Aug;460:319-32; , Mirkovic N et al. Cancer Res., 2004 Jun;64:3790-7; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90). Two other alterations at the same codon, p.D1739E (c.5217T>G) and p.D1739H (c.5215G>C), have been described in probands w/ HBOC-associated cancers and found to be deficient in functional studies (Lee MS et al. Cancer Res, 2010 Jun;70:4880-90; Woods NT et al. NPJ Genom Med, 2016 Mar;1; Findlay GM et al. Nature, 2018 10;562:217-222; Ha HI et al. J Gynecol Oncol, 2020 Nov;31:e83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Aug 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glycine at codon 1739 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, transcription activation, human haploid cell proliferation and rescue of Brca1-deficient mouse embryonic stem cells in growth and cisplatin and PARP inhibitor sensitivity assays (PMID: 20516115, 30209399. 32546644). This variant has been observed in at least two individuals affected with breast cancer (PMID: 19491284, 33471991; Leiden Open Variation Database DB-ID BRCA1_000426) and several suspected breast and ovarian cancer families (PMID: 9333265, 12827452, 19949876), and it has been reported to cosegregate with disease (PMID: 15800311). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Malignant tumor of breast Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Asp1739Gly variant was identified in 5 of 3114 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (van Harssel 2010, Rostagno 2003, Haffty 2009, Shattuck-Eidens 1997). The variant was also identified in dbSNP (ID: rs80357227) as "With Likely pathogenic, Pathogenic allele", ClinVar (classified as likely pathogenic by Invitae and GeneDx; as uncertain significance by two submitters), COGR, MutDB, UMD-LSDB (1x as unclassified variant), and in BIC Database (2x with unknown significance). The variant was not identified in Cosmic, ARUP Laboratories, Zhejiang University databases, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Asp1739 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional studies, including in vitro protein folding, phosphopeptide-binding, and cell-based transcriptional assays, predict this variant to be disease associated and classified as deleterious (Karchin 2007, Mirkovic 2004, Lee 2010, Bouwman 2013, Coyne 2004). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 15004537, 20516115, 23867111, 30209399, 32546644). 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. ClinVar contains an entry for this variant (Variation ID: 55465). This variant is also known as A5335G. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 12827452, 15800311, 19491284, 19949876). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1739 of the BRCA1 protein (p.Asp1739Gly). -

Breast and/or ovarian cancer Uncertain:1

Dec 21, 2012

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.;.;T;T;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.9	D;N;.;D;.;.;N;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D;D;.;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.0010, 1.0	.;B;.;.;.;D;.;.
Vest4		0.98
MVP		0.87
MPC		0.16
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.84
gMVP		0.82

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: rs80357227; hg19: chr17-41209130;