chr17-43094422-ACAT-A

Position:

• chr17-43094422-ACAT-A

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.1106_1108delATG​(p.Asp369del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: BRCA1 NM_007294.4 disruptive_inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:1 B:14
• Conservation: PhyloP100: 1.21

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 (HGNC:):

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 17-43094422-ACAT-A is Benign according to our data. Variant chr17-43094422-ACAT-A is described in ClinVar as [Benign]. Clinvar id is 54130.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094422-ACAT-A is described in Lovd as [Benign]. Variant chr17-43094422-ACAT-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1106_1108delATG	p.Asp369del	disruptive_inframe_deletion	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1106_1108delATG	p.Asp369del	disruptive_inframe_deletion	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251166 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461844 Hom.: 0 AF XY: 0.000105 AC XY: 76 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

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: 0.000129

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Mar 25, 2013	- -
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 = 3.98E-07 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	May 21, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Asp369del variant is an in-frame deletion resulting in the removal of an aspartic acid (Asp) residue at codon 369. The variant was identified in at least 11 of 116044 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer, and was not identified in 360 control chromosomes from healthy individuals (Borg 2010, Chenevix-Trench 2006 16489001, Couch 1996, Judkins 2005); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant is listed in dbSNP (ID: rs80358326) “With untested allele”; however, no frequency information was available for the variant. The variant was also identified in HGMD, LOVD, and the BIC database (2X with unknown clinical importance), and the ClinVar database (with one “uncertain significance” classification from BIC, and an unclassified submission from Invitae). Judkins (2005) identified this variant in trans with a known deleterious BRCA1 mutation (5385insC), increasing the likelihood that the p.Asp369del variant does not have clinical significance. A study by Chenevix-Trench (2006) demonstrated loss of the variant allele in tumours, suggesting that this variant is neutral. In addition, three multifactorial probability based models predict this to be a neutral variant (Chenevix-Trench 2006, Easton 2007, Lindor 2012). 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 predicted benign. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2019	This alteration is classified as likely 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	curation	Sema4, Sema4	Jun 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 01, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2020	This variant is associated with the following publications: (PMID: 11044354, 19941162, 27153395, 8807330, 21990134, 17924331, 22753008, 20104584, 16267036, 16489001) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 04, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 23, 2020

Variant summary: BRCA1 c.1106_1108delATG (p.Asp369del) results in an in-frame deletion that is predicted to remove an Asp amino acid from the encoded protein. The variant allele was found at a frequency of 5.3e-05 in 245906 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (5.3e-05 vs 0.001), allowing no conclusion about variant significance. c.1106_1108delATG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Chenevix-Trench_2006) that indicates the variant co-occurred in trans with a pathogenic BRCA1 variant, although the variant was not specified. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.4409_4410delTA, p.I470fsX11; BRCA2 c.7180A>T, p.Arg2394X), providing supporting evidence for a benign role. Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer and co-segregation with disease in pedigrees (when available), predicted this variant to be neutral (Easton 2007, Lindor 2012). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. In addition, one expert panel classified this variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

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

Sep 16, 2015

- -

Ovarian cancer Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Asp369del variant is an in-frame deletion resulting in the removal of an aspartic acid (Asp) residue at codon 369. The variant was identified in at least 11 of 116044 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer, and was not identified in 360 control chromosomes from healthy individuals (Borg 2010, Chenevix-Trench 2006 16489001, Couch 1996, Judkins 2005); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant is listed in dbSNP (ID: rs80358326) ?With untested allele?; however, no frequency information was available for the variant. The variant was also identified in HGMD, LOVD, and the BIC database (2X with unknown clinical importance), and the ClinVar database (with one ?uncertain significance? classification from BIC, and an unclassified submission from Invitae). Judkins (2005) identified this variant in trans with a known deleterious BRCA1 mutation (5385insC), increasing the likelihood that the p.Asp369del variant does not have clinical significance. A study by Chenevix-Trench (2006) demonstrated loss of the variant allele in tumours, suggesting that this variant is neutral. In addition, three multifactorial probability based models predict this to be a neutral variant (Chenevix-Trench 2006, Easton 2007, Lindor 2012). 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. -

BRCA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

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

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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: rs80358325; hg19: chr17-41246439;