17-43047654-T-C

Position:

• chr17-43047654-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):​c.5456A>G​(p.Asn1819Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10 O:1
• Conservation: PhyloP100: -1.00

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 -10 ACMG points.

• PM1: In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.040658474).
• BP6: Variant 17-43047654-T-C is Benign according to our data. Variant chr17-43047654-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 55585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5456A>G	p.Asn1819Ser	missense_variant	22/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5456A>G	p.Asn1819Ser	missense_variant	22/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000398 AC: 10 AN: 251488 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000711 AC: 104 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000701 AC XY: 51 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000836

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 15, 1997	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	This variant is associated with the following publications: (PMID: 20516115, 17305420, 10946236, 26689913, 15172985, 30209399, 33087888, 31825140) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2016	Variant summary: The BRCA1 c.5456A>G variant affects a non-conserved nucleotide, resulting in amino acid change from a medium size and polar Asparagine (N) to a small size and polar Serine (S). 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). Functional assays support these in silico predictions of a benign outcome. Homology directed recombination is not impaired by this missense mutation (Lu_BRCA_Nature Comms_2015), nor is the activity of this BRCT domain variant in transcriptional activation (Lee_CR_2010 ) . Pavlicek et al._2004 predicted the variant to lead to a conservative substitution also implicating a neutral outcome. This variant was found in 4/121402 control chromosomes at a frequency of 0.0000329, which does not significantly exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). There is at least one HBOC family reported to have the variant in the literature but this report lacks clinical, co-segregation, and control data, therefore it does not permit establishment of a cause-effect relationship between the variant and HBOC (Judkins_Cancer Res_2005). In addition, several reputable clinical laboratories classified this variant as benign without evidence to independently evaluate. There have been no reports of pathogenic co-occurrences in patients. Functional evidence strongly support a benign outcome, thus this missense BRCA1 variant is classified as likely benign until co-occurrence or co-segregation data are available. -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 31, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 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. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.059
DANN	Benign	0.20
DEOGEN2	Benign	0.093	.;T;.;T;T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.72	T;T;T;T;T;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.041	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.16	N;N;.;.;.;.;N;N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T;T;.;.;.;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;B;.;.;.;B;.;.
Vest4		0.20
MVP		0.36
MPC		0.065
ClinPred		0.0041	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs80357286; hg19: chr17-41199671; COSMIC: COSV58794902;