rs80358329

chr17-43093682-TAGA-Tchr17-43093682-TAGA-TAGAAGA

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PM4_Supporting BP6_Very_Strong

The NM_007294.4(BRCA1):c.1846_1848del(p.Ser616del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,614,142 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S616S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: BRCA1 NM_007294.4 inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:1 B:20
• Conservation: PhyloP100: 3.57

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 Benign. Variant got -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_007294.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 17-43093682-TAGA-T is Benign according to our data. Variant chr17-43093682-TAGA-T is described in ClinVar as [Benign]. Clinvar id is 37430.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093682-TAGA-T is described in Lovd as [Pathogenic]. Variant chr17-43093682-TAGA-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1846_1848del	p.Ser616del	inframe_deletion	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1846_1848del	p.Ser616del	inframe_deletion	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD3 exomes AF: 0.000267 AC: 67 AN: 251132 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135780

Gnomad AFR exome AF: 0.00377

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1461806 Hom.: 1 AF XY: 0.000127 AC XY: 92 AN XY: 727198

Gnomad4 AFR exome AF: 0.00466

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000872 AC XY: 65 AN XY: 74504

Gnomad4 AFR AF: 0.00329

Gnomad4 AMR AF: 0.000131

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

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.00104

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:20

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Feb 05, 2014	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Benign, 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 1 based on posterior probability = 5.40E-06 -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2020	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Ser616del variant is an in-frame deletion resulting in the removal of a serine (Ser) residue at position 616; the impact of this alteration on BRCA1 protein function is not known. It has been identified in the literature in 9 of 6508 proband chromosomes (frequency: 0.001) from Nigerian, Sudanese, Moroccan, British and African- American individuals with breast cancer and HBOC and was present in 3 of the 506 control chromosomes (frequency: 0.006) from healthy individuals (Fackenthal 2012, Biunno 2014, Borg 2010, Ellis 2000, Judkins 2005a, McKean-Cowdin 2005, Tazzite 2012). The variant was identified in control databases in 103 of 282534 chromosomes (0 homozygous) at a frequency of 0.0003646, and was observed at the highest frequency in the African population in 97 of 24900 chromosomes (freq: 0.003896) (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was identified in ClinVar (Benign, reviewed by expert panel. Classified as benign by ENIGMA, Ambry Genetics, Michigan Medical Genetics Laboratories, Quest Diagnostics, Invitae, SCRP. Classified as likely benign by ARUP Laboratories, GeneDx, Michigan Medical Genetics Laboratories, Mendelics, CHEO, Color, Institute for Biomarker Research Medical Diagnostic Laboratories, Prevention Genetics, Quest Diagnostics. Classified as VUS by Fulgent, BIC). The variant was also identified in dbSNP (ID: rs rs80358329), ARUP Laboratories BRCA Mutations Database (classification definitely pathogenic based on a publication from 2000), and UMD (3X with “unclassified variant” classification). Myriad classifies this as a polymorphism (personal communication). The variant was identified with a co-occurring pathogenic BRCA1 variant (1755del19), increasing the likelihood that the p.Ser616del variant does not have clinical significance (Judkins 2005). The deletion variant localizes to a highly conserved region that interacts with several regulating proteins, however, it was found to occur in both affected and unaffected siblings in an African-American sibship (McKean-Cowdin 2005), but was not identified in controls in a British study looking at BRCA1 mutations in early onset/no family history of breast/ovarian cancer cases (Ellis 2000). 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 benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22874498, 19941162, 30263132, 11183185, 15726418, 20104584, 22034289, 24729269, 22425665, 16267036, 29892687, 31131967) -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 16, 2014	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 04, 2021	- -

Hereditary breast ovarian cancer syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 30, 2017

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

BRCA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs80358329; hg19: chr17-41245699;