rs80358344

Variant names:

• chr17-43067617-TAAC-T
• rs80358344
• NM_007294.4:c.5062_5064delGTT

Your query was ambiguous. Multiple possible variants found:

• chr17-43067617-TAAC-T
• chr17-43067617-TAAC-TAACAAC

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5062_5064delGTT​(p.Val1688del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000657 in 152,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000076766: Experimental studies have shown that this variant affects BRCA1 function (PMID:11157798, 19706752, 23867111)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V1688V) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: BRCA1 NM_007294.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:14 U:2
• Conservation: PhyloP100: 5.60
• Publications: 32 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000076766: Experimental studies have shown that this variant affects BRCA1 function (PMID: 11157798, 19706752, 23867111).; SCV001360567: Functional studies reports this variant affects protein stability, DNA damage response, association with BRCA1 partner proteins and transcriptional activity (Vallon-Christersson_2001, De Nicolo_2009).; SCV001553218: Using multi modal analysis approach, comprising comparative structural modeling, analysis of protein stability and associations, and analysis of DNA repair function, predicted BRCT domain destabilization and folding disruption caused by BRCA1 p.V1688del. Consistently, the recombinant delta ValBRCA1 was less stable than wtBRCA1 and, unlike the latter, failed to associate with BRIP1, CtIP, and Rap80, and to re-localize to sites of DNA damage. Yeast two-hybrid analysis revealed a compromised interaction with FHL2 and with KPNA2, which is likely responsible for improper subcellular localization of delta ValBRCA1. They concluded the variant is deleterious impairing protein stability and function (DeNicolo 2009).; SCV000185316: "In addition, functional analyses have shown that this alteration leads to a protein that partially disrupts the BRCA1 BRCT domain, compromises protein stability, displays deficient DNA damage response function, and fails to associate with known partner proteins (De Nicolo, A et al. Cancer Res. 2009 Sep 1;69(17):7030-7). Furthermore, a yeast-based transcriptional assay showed that this alteration displayed no transcriptional activity compared to wildtype (Vallon-Christersson, J et al. Hum Mol Genet. 2001 Feb 15;10(4):353-60)."; SCV000683244: Functional studies have reported that this variant impacts BRCA1 function in transcription activation and may impact protein stability (PMID: 11157798, 19706752, 21447777).; SCV000293207: Functional studies by Bouwman et al. (2013) have suggested that BRCA1 Val1688del is pathogenic based on its inability to rescue the proliferation defect in BRCA1 deficient mouse embryonic stem cells and a statistically significant increase in sensitivity to cisplatin compared to controls. Additional functional assessments have demonstrated that BRCA1 Val1688del disrupts interactions with known partner proteins (De Nicolo 2009) and causes deficient transactivation activity (Vallon-Christersson 2001).; SCV004219436: "In functional studies, the variant has been found to be damaging to transcriptional activity (PMID: 11157798 (2001)), damaging to stability, interaction with other proteins, and HDR activity (PMID: 19706752 (2009), and damaging in mouse embryonic stem cells and cisplatin response (PMID: 23867111 (2013))".
• PM1: In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 79 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_007294.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-43067617-TAAC-T is Pathogenic according to our data. Variant chr17-43067617-TAAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 55368.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5062_5064delGTT	p.Val1688del	conservative_inframe_deletion	Exon 16 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5128_5130delGTT	p.Val1710del	conservative_inframe_deletion	Exon 17 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5128_5130delGTT	p.Val1710del	conservative_inframe_deletion	Exon 17 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5062_5064delGTT	p.Val1688del	conservative_inframe_deletion	Exon 16 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5125_5127delGTT	p.Val1709del	conservative_inframe_deletion	Exon 17 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5062_5064delGTT	p.Val1688del	conservative_inframe_deletion	Exon 16 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2110

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (9)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=47/53	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs80358344; hg19: chr17-41219634;