rs80358344

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5062_5064del​(p.Val1688del) variant causes a 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. V1688V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: BRCA1 NM_007294.4 inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:13 U:2
• Conservation: PhyloP100: 5.60

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 13 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 17 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 id is 55368.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067617-TAAC-T is described in Lovd as [Pathogenic]. Variant chr17-43067617-TAAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5062_5064del	p.Val1688del	inframe_deletion	16/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5062_5064del	p.Val1688del	inframe_deletion	16/23	1	NM_007294.4	P4

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 19, 2022	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.998076 -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Val1688del is an in-frame deletion variant and was identified in 9 of 122 proband chromosomes (frequency: 0.074) from individuals or families of Italian descent with breast and ovarian cancer (Ramunas-Janavicius 2010). The variant was also identified in dbSNP (ID: rs80358344) a “With Pathogenic allele”; ClinVar and Clinvitae databases (Pathogenic by Ambry Genetics, GeneDx and Uncertain significance by Breast Cancer Information Core (BIC)); ARUP Laboratories BRCA Mutations Database (1X Definitely pathogenic); COGR database (unknown significance by MESHWCRI and likely pathogenic by CVH); BIC database (6X with unknown clinical importance); The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict altered splicing; this is not very predictive of pathogenicity. Several functional and co-segregation studies provide evidence that the p.Val1688del is deleterious. 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). An analysis, integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data, a final score of 349,000:1 in favor of disease causality was obtained. In one family the variant co-segregated with 6/6 breast cancer affected sisters and was not found in 2 healthy sisters who had not inherited the variant. In another family all affected members carried the mutation including a maternal aunt with cervical cancer (Malacrida 2008). Several lines of evidence have suggested that BRCA1 as a transcription regulator and it has been demonstrated that disease-associated mutations abolish the transactivation by BRCA1 in different experimental systems. The V1688del variant displayed loss of activity suggesting that it represents a cancer-associated mutation (Vallon-Christersson 2001). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 07, 2015	- -
Pathogenic, no assertion criteria provided	research	Medical Genetics, Medical University Pleven	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2022	The frequency of this variant in the general population, 0.0000066 (1/152162 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 11157798 (2001), 18165637 (2008), 18821011 (2009), 19706752 (2009), 22425665 (2012), 26306726 (2015), 27153395 (2016)). 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)). Reputable multifactorial analyses have also indicated causality of this variant to disease (PMID: 17924331 (2007), 21990134 (2012), 31131967 (2019)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2017	This in-frame deletion of three nucleotides in BRCA1 is denoted c.5062_5064delGTT at the cDNA level and p.Val1688del (V1688del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 5181_5183delGTT or c.5062_5064del. The normal sequence, with the bases that are deleted in braces, is TGTT[GTT]ATGA. This deletion of a single Valine residue occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located within the BRCT1 domain (Narod 2004). BRCA1 Val1688del has been observed in familial breast and/or ovarian cancer cases (Montagna 1996, Malacrida 2008, Tazzite 2012) and was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. 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). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2023	This variant causes the in-frame deletion of one amino acid, valine 1688, in the BRCT domain of the BRCA1 protein. Functional studies have reported that this variant impacts BRCA1 function in transcription activation and may impact protein stability (PMID: 11157798, 19706752, 21447777). This variant has been detected in over 15 individuals and families affected with breast and ovarian cancer (PMID: 8968102, 18165637, 18821011, 22425665, 26306726, 27153395), and it has been reported as a founder mutation in Italy based on haplotype analysis (PMID: 18165637, 18821011). This variant also has been observed to cosegregate with disease with odds for pathogenicity of 661:1 (PMID: 18165637) and a likelihood ratio of pathogenicity of 16.93 (PMID: 31131967). 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 24, 2021	The c.5062_5064delGTT pathogenic mutation (also known as p.V1688del) is located in coding exon 15 of the BRCA1 gene. This pathogenic mutation results from an in-frame GTT deletion at nucleotide positions 5062 to 5064. This results in the in-frame deletion of a valine at codon 1688. This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Lindor, NM et al. Hum Mutat. 2012 Jan;33(1):8-21; Easton DF et al. Am. J. Hum. Genet., 2007 Nov;81:873-83). This alteration has been identified in multiple breast and ovarian cancer families and has been described as an Italian founder mutation (Montagna, M et al. Cancer Res. 1996 Dec 1;56(23):5466-9; De Nicolo, A et al. Cancer Res. 2009 Sep 1;69(17):7030-7; Tazzite A et al. Gynecol. Oncol., 2012 Jun;125:687-92; Minucci A et al. Expert Rev. Mol. Diagn., 2015 Aug;15:1383-403; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-17). In one family this alteration segregated with disease in six of six affected sisters and was absent in two healthy relatives (Malacrida, S et al. J Clin Oncol. 2008 Jan 1;26(1):26-31). 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). This alteration has also been classified as likely to be deleterious based on a interspecific sequence variation classification system (Abkevich V et al. J. Med. Genet., 2004 Jul;41:492-507). A computational study reported this alteration as pathogenic based on data derived from an in vitro functional assay (Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88). Of note, this alteration is also designated as 5181del3 in published literature. Based on the available evidence, c.5062_5064delGTT is classified as a pathogenic mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This variant, c.5062_5064del, results in the deletion of 1 amino acid(s) of the BRCA1 protein (p.Val1688del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8968102, 18165637, 18703817, 18821011, 19706752, 23697973, 25814778, 26306726). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55368). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Experimental studies have shown that this variant affects BRCA1 function (PMID: 11157798, 19706752, 23867111). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 24, 2019	Variant summary: BRCA1 c.5062_5064delGTT (p.Val1688del) results in an in-frame deletion that is predicted to remove one conserved hydrophobic residue (Valine) from the encoded protein and located in beta3 in the BRCT-N domain (Vallon-Christersson_2001). The variant was absent in 251360 control chromosomes (gnomAD). c.5062_5064delGTT has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Vallon-Christersson_2001, Malacrida_2008, De Nicolo_2009). In addition, this variant was co-segregated with disease in multiple families (Malacrida_2008, De Nicolo_2009). These data indicate that the variant is very likely to be associated with disease. 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). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

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: rs80358344; hg19: chr17-41219634;