rs80357087

Variant names:

• chr17-43067677-C-A
• rs80357087
• NM_007294.4:c.5005G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43067677-C-A
• chr17-43067677-C-G
• chr17-43067677-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP6

The NM_007294.4(BRCA1):​c.5005G>T​(p.Ala1669Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000093 in 1,612,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A1669T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:17 O:1
• Conservation: PhyloP100: 4.72

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 1 ACMG points.

• PM1: In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
• BP6: Variant 17-43067677-C-A is Benign according to our data. Variant chr17-43067677-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41831.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Benign=2, Uncertain_significance=2, not_provided=1}. Variant chr17-43067677-C-A is described in Lovd as [Likely_benign]. Variant chr17-43067677-C-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5005G>T	p.Ala1669Ser	missense_variant	Exon 16 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5005G>T	p.Ala1669Ser	missense_variant	Exon 16 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152028 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

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: 0.000382

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251344 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135858

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1460484 Hom.: 0 Cov.: 30 AF XY: 0.0000908 AC XY: 66 AN XY: 726674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152028 Hom.: 0 Cov.: 30 AF XY: 0.000135 AC XY: 10 AN XY: 74256

Gnomad4 AFR AF: 0.0000242

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: 0.000382

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000466 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:17 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: BS3:Supporting -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 23, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide with 3/4 in silico programs (SNPs&Go effect not captured here due to low reliability index) predict a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 6/121254 (1/20210), which does not exceed the predicted maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in affected individuals via publications including a co-occurrence with another pathogenic BRCA1 variant 2080delA (Judkins_2005) and a lack of co-segregation with disease (Vallon-Christersson_2001). Multiple functional studies showed the variant of interest to act comparable to wild type. In addition, multiple reputable databases/clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

not specified Uncertain:1 Benign:3

Jun 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple reports describe as nonpathogenic; ClinVar: 4 B/LB, 2 VUS -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 26, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 26, 2014

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Hereditary cancer-predisposing syndrome Benign:3

Jul 20, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 09, 2022

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast and/or ovarian cancer Benign:2

Apr 24, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Breast carcinoma Uncertain:1

Nov 13, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Ala1669Ser variant was identified in 1 of 208 proband chromosomes (frequency: 0.005) from individuals or families with breast and ovarian cancer (Stegel 2011).The variant was also identified in dbSNP (ID: rs80357087) “With Uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a uncertain significance variant by the BIC, Biesecker Laboratory; classified as likely benign by Ambry Genetics, CSER_CC_NCGL, GeneDX, Counsyl), the BIC database (11X with unknown clinical importance), and UMD (1X as a UV variant).This variant was identified in the Exome Variant Server project in 1 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 6 of 77032 chromosomes (6 individuals) from a population of European (Non-Finnish /African individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ala1669 residue is 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 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. Comprehensive analysis study by Lee (2010) identified the variant score no protein folding defect, normal peptide binding activity and specificity, and normal transcriptional activity. The study by Rowling (2010) used biophysical approach to classify the variant and suggested the variant does not have destabilizing effect. Furthermore, conservation analysis by Abkevich (2004) classified the variant as likely to be neutral or of little clinical significance. In addition, this variant was identified in trans with known deleterious mutations (2080delA) (Judkins 2005), increasing the likelihood this variant does not have clinical significance. 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. -

Familial cancer of breast Benign:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PM1,PP3,BP6,BS1. -

Hereditary breast ovarian cancer syndrome Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;.;N;.;N;N;N;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.063	T;D;.;T;.;D;T;D;T;T
Sift4G	Benign	0.26	T;D;D;T;D;D;T;.;.;D
Polyphen		0.64, 1.0	.;P;.;.;.;.;.;.;D;.
Vest4		0.66
MVP		0.88
MPC		0.13
ClinPred		0.28	T
GERP RS		5.2
Varity_R		0.80
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80357087; hg19: chr17-41219694; COSMIC: COSV99070453;