rs1799966

chr17-43071077-T-Achr17-43071077-T-Cchr17-43071077-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM5 BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):c.4837A>T(p.Ser1613Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1613A?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: -0.194

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 -8 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43071076-CT-GGC is described in ClinVar as [Pathogenic]. Clinvar id is 180697.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17928162).
• BP6: Variant 17-43071077-T-A is Benign according to our data. Variant chr17-43071077-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 37613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4837A>T	p.Ser1613Cys	missense_variant	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4837A>T	p.Ser1613Cys	missense_variant	15/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000677

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251384 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135858

Gnomad AFR exome AF: 0.000800

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461884 Hom.: 0 Cov.: 59 AF XY: 0.0000124 AC XY: 9 AN XY: 727240

Gnomad4 AFR exome AF: 0.000538

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: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.000243 AC XY: 18 AN XY: 74216

Gnomad4 AFR AF: 0.000677

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: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 06, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 07, 2021	- -

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

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 14, 2011	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	Variant summary: BRCA1 c.4837A>T (p.Ser1613Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251384 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.4837A>T has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome (Majdak_2005, D'Argenio_2015, Cifuentes-C_2019, Cecener_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant is likely not pathogenic (Woods_2016, Fernandes_2019). The following publications have been ascertained in the context of this evaluation (PMID: 18992264, 31706072, 32284662, 15004537, 25896959, 30765603, 15617999, 9326340, 15350310, 28781887). ClinVar contains an entry for this variant (Variation ID: 37613). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 18, 2019	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 18, 2020

This variant is associated with the following publications: (PMID: 26092435, 31705708, 15004537, 15350310, 19370767, 10728701, 21447777, 18992264, 25896959, 15617999, 9326340, 26183948, 28781887, 30765603, 31706072) -

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.Ser1613Cys variant was identified in 1 of 140 proband chromosomes (frequency: 0.007) from individuals or families with breast cancer (D'Argenio 2015). The variant was also identified in dbSNP (rs1799966) as “other”, in ClinVar with conflicting interpretations of pathogenicity (5 submitters, classified as Likely Benign by Invitae, Ambry, and GeneDx, classified as Uncertain Significance by BIC and as Benign by the Sharing Clinic Reports Project), in Clinvitae (classified as Likely benign as reported in ClinVar) and in BIC (4x classified as unknown), the Fanconi Anemia Mutation Database (3x classified as predicted neutral) databases. The variant was also identified in the control database the Exome Aggregation Consortium (ExAC) in 8 of 121360 chromosomes (freq. 0.00007), all cases were seen in the African population specifically 8 of 10406 chromosomes (freq. 0.0008), increasing the likelihood that this may be a low frequency benign variant. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the ARUP Laboratories BRCA Mutations Database, COSMIC, GeneInsight COGR, and UMD. Functional studies initially reported the p.Ser1613Cys variant to be disease causing based on a transcription activation assay performed in yeast (Monteiro 1997). However a more recent and more sensitive transcriptional assay reported the p.Ser1613Cys variant to be likely neutral and noted that the sensitivity of the previous assay was likely the reason for the conflicting results (Carvalho 2009). The p.Ser1613 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. Moreover this locus is the known site of a common polymorphism in BRCA1 p.Ser1613Gly (identified in 35% of cases in ExAC) and classified as Benign by our laboratory. 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 a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 01, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.022	D
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.0	D;N;.;N;.;N;D;D;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;T;D;D;D;.;.;T
Polyphen		0.98, 0.98	.;D;.;.;.;.;.;.;D;.
Vest4		0.31
MVP		0.78
MPC		0.37
ClinPred		0.095	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.087
gMVP		0.32

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: rs1799966; hg19: chr17-41223094;