rs80357102

Positions:

• chr17-43106469-C-A
• chr17-43106469-C-G
• chr17-43106469-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):​c.199G>T​(p.Asp67Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,596,780 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 Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:19 O:1
• Conservation: PhyloP100: 0.0330

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19060779).
• BP6: Variant 17-43106469-C-A is Benign according to our data. Variant chr17-43106469-C-A is described in ClinVar as [Benign]. Clinvar id is 54431.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43106469-C-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.199G>T	p.Asp67Tyr	missense_variant	4/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.199G>T	p.Asp67Tyr	missense_variant	4/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000719 AC: 18 AN: 250382 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

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: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000852 AC: 123 AN: 1444464 Hom.: 0 Cov.: 28 AF XY: 0.0000834 AC XY: 60 AN XY: 719438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

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: 0.000108

Gnomad4 OTH exome AF: 0.0000502

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74478

Gnomad4 AFR AF: 0.0000240

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000794 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:4 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 24, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	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 = 0.0000029 -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Oct 13, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 07, 2007	- -
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 specified Benign:7

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -

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	curation	Sema4, Sema4	Aug 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 28, 2016	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 27, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2017	Variant summary: This missense variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a pathogenic outcome. The variant is present at a low frequency in the control population (0.0076% in ExAC, 0.012% in European (Non-Finnish)), and has been reported in the literature in HBOC patients and families. Most of these publications, however, fail to provide co-segregation and co-occurrence data, and do not test for large deletions/insertions, and therefore do not provide strong evidence for the causality of this variant. In addition, one report, although a poster presentation, is provided by individuals from a reputable laboratory, Myriad, indicating the variant was found to co-occur with 9 pathogenic variants (gene and variants not specified) and was classified as benign. UMD lists variant in 15 individuals with classification of "1-Neutral". One of them carried a pathogenic BRCA2 variant c.1773_1776delTTAT (p.Ile591MetfsX22). Furthermore, several functional studies have been published and showed that the c.199G>T variant had a moderate effect on centrosome duplication (Kais_2012, Towler_2013), chromosomal instability, (Cochran_2015), and resulted in a moderate reduction in E3 ligase activity, but that the mutant protein had similar binding of BRCA1 to BARD1 (Caleca_2014, Ransburgh_2010, Morris_2006, Starita_2015) and wild-type levels of E2 interaction (Morris_2006). There was no difference in homologous recombination (Kais_2012, Ransburgh_2010), double strand break repair by the single-strand annealing pathway (Towler_2013), yeast colony size, spot formation, and yeast localization (Thouvenot_2016) between mutant BRCA1 with this variant and wild-type BRCA1. This variant also had no effect on splicing via patient cDNA and minigene splicing assay (Houdayer_2012, Thery_2011). Additionally, multifactorial probability based models showed a low odds in favor of causality (Lindor_2012, Easton_2007). In addition, multiple reputable databases, UMD, ARUP, and clincial labs classify the variant as "benign/likely benign, at-least 2 of whom have submitted/updated their submissions to ClinVar since the time of the previous classification of this variant in our laboratory." Therefore, taking all evidence into consideration, the variant of interest is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2017	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

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 04, 2021

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Asp67Tyr variant was identified in 4 of 1760 proband chromosomes from individuals or families with breast or ovarian cancer (Blay 2013, Diez 2003); however, control chromosomes from healthy individuals were not evaluated in these studies. The variant was also identified HGMD, LOVD, the BIC database (8X with unknown clinical importance), and UMD (15X as a neutral variant). In UMD, the variant was found to co-occur with a pathogenic BRCA2 mutation (c.1773_1776delTTAT (p.Ile591MetfsX22)) in one sample, increasing the likelihood that the p.Asp67Tyr variant may not have clinical significance. The variant was listed in dbSNP (ID: rs80357102) “With allele of Uncertain significance”, with a minor allele frequency of 0.0005 (1000 Genomes Project), and in the NHLBI Exome Sequencing Project (Exome Variant Server) in 2 of 8582 European American alleles; however the low number and frequency of this variant in these populations is not substantive enough to determine the prevalence of this variant in the general population. This residue is not conserved in mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Several function studies found the variant to have a neutral effect on BRCA1 function, including assays evaluating protein binding, homology directed recombination, and single-strand annealing repair (Atipairin 2011, Bouwman 2013, Caleca 2014, Morris 2006, Ransburgh 2010, Towler 2013). One study found that the variant had an intermediate effect on centrosome amplification; however, the authors suggest that this may be on the high end of the normal range (Kais 2012). In addition, two in silico studies using multifactorial probability based models found this variant to be neutral (Easton 2007, Lindor 2012). Furthermore, Myriad classifies this variant as “Favor polymorphism” (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.062	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	0.43	T
PROVEAN	Benign	-1.9	N;N;N;D;N;D;D;N;N;.;N;N;D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.017	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.022	D;D;D;D;D;D;.;D;D;.;D;D;.;.
Polyphen		0.87, 0.57, 0.52	.;P;.;.;.;P;.;.;P;.;.;.;.;.
Vest4		0.61
MVP		0.86
MPC		0.10
ClinPred		0.039	T
GERP RS		-1.4
Varity_R		0.29
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs80357102; hg19: chr17-41258486; COSMIC: COSV105897737; COSMIC: COSV105897737;