rs80356994

chr17-43124078-G-Achr17-43124078-G-Cchr17-43124078-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_007294.4(BRCA1):c.19C>T(p.Arg7Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12 O:1
• Conservation: PhyloP100: 1.36

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 14 uncertain in NM_007294.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.32959718).
• BP6: Variant 17-43124078-G-A is Benign according to our data. Variant chr17-43124078-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37440.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=9, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.19C>T	p.Arg7Cys	missense_variant	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.19C>T	p.Arg7Cys	missense_variant	2/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251054 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135680

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: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461164 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 20 AN XY: 726934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:2 Other:1

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 25, 2011	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2018	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, no assertion criteria provided	clinical testing	True Health Diagnostics	Mar 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 04, 2017	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2023	Variant summary: BRCA1 c.19C>T (p.Arg7Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.19C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples- Gonzalez_2011, Keshvarzi_2012, Solano_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant, suggesting a benign functional effect (examples Starita_2015, Bouwman_2020), and has been reported to not have an effect on splicing (Wai_2020). The variant has also been reported to have normal binding to BARD1 and E2, and have normal levels of E3 ligase activity (Morris_2006). The following publications have been ascertained in the context of this evaluation (PMID: 32546644, 20683152, 35659930, 30209399, 20859677, 34981296, 16267036, 21918854, 16403807, 23192404, 23961350, 25823446, 32123317). Seven other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant with a majority consensus as as likely benign (n=6) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 05, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2020	This variant is associated with the following publications: (PMID: 20859677, 23961350, 26109977, 11573085, 23192404, 21918854, 32123317, 22684231, 16403807, 24312913, 25823446, 30209399, 31131967) -

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

Jan 05, 2023

- -

BRCA1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 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). -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Arg7Cys variant was identified in 5 of 516 proband chromosomes (frequency: 0.0097) from Argentinean, Iranian and Algerian individuals or families with HBOC (Cherbal 2012, Solano 2012, Keshavarzi 2012). The variant was also identified in dbSNP (ID: rs80356994) as "With other allele", ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Color, Invitae, Quest Diagnostics, SCRP, and True Health Diagnostics; as uncertain significance by Queen's University and BIC), LOVD 3.0 (3 submissions, classified as does not affect function and effect unknown), UMD-LSDB (classified as a probable polymorphism).The variant was identified in control databases in 6 of 245822 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 6 of 111308 chromosomes (freq: 0.000054), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In a yeast two-hybrid ubiquitin ligase assay this variant showed E2 and BARD1 binding and E3 ligase activity equivalent to wild type function (Morris 2006). In a massively parallel functional analysis of BRCA1 RING domain variants, this variant showed no binding defect with BARD1 and was able to rescue homology-directed DNA repair but it performed poorly in the E3 ligase selections; however, it may retain enough E3 ligase activity to satisfy a possibly low threshold of requisite activity and was classified as benign (Starita 2015). The p.Arg7 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.015
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.3	L;L;L;L;L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.71	N;N;N;N;N;N;N;.;N;N;N;D;D;.
REVEL	Uncertain	0.56
Sift	Benign	0.048	D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;D;.;D;.;D;.;.;.
Polyphen		0.99, 1.0, 0.99	.;D;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.48
MVP		0.87
MPC		0.29
ClinPred		0.28	T
GERP RS		2.8
Varity_R		0.25
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs80356994; hg19: chr17-41276095; COSMIC: COSV100524047; COSMIC: COSV100524047;