17-43091971-C-T

Position:

chr17-43091971-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5BP4_ModerateBP6

The NM_007294.4(BRCA1):c.3560G>A(p.Ser1187Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. S1187T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 0.498

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.17115301).

BP6

Variant 17-43091971-C-T is Benign according to our data. Variant chr17-43091971-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54917.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.3560G>A	p.Ser1187Asn	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.3560G>A	p.Ser1187Asn	missense_variant	10/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250932

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 07, 2017	Variant summary: The BRCA1 c.3560G>A (p.Ser1187Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index) with one in-silico predictive study on the protein function predicting this variant to be deleterious (Pavlicek_HMG_2004). The variant of interest has been found in a large, broad control population, ExAC in 3/120606 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant was reported in breast cancer patients without strong evidence for causality (Miller-Samuel_BRCA_SO_2011, Lee_BRCA2_BCR_2008, Schenkel_BRCA1&2_JMD_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until more definitive clinical and functional data become available. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 14, 2023	In the published literature, this variant has been reported in individuals/families with breast cancer (PMID: 30287823 (2018), 21810505 (2011), 18284688 (2008)). This variant has also been reported in an elderly cancer free individual (PMID: 32658311 (2011)). In addition, this variant is located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000087 (3/34524 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2024	Observed in individuals with personal or family history of breast and/or ovarian cancer, as well as in unaffected controls (PMID: 30287823, 27376475, 21810505, 32658311, 18284688); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3679G>A; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21810505, 27376475, 30287823, 15385441, 32377563, 31131967, 29884841, 31853058, 32658311, 18284688) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 06, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 24, 2022	The p.S1187N variant (also known as c.3560G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3560. The serine at codon 1187 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in a population-based study of early-onset breast cancer diagnoses (Lee E et al. Breast Cancer Res. 2008 Feb;10:R19). This alteration was also observed in 1/7,051 unselected female breast cancer patients and was not observed in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer. 2021 01;148:285-295). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Breast Cancer Information Core (BIC) (BRCA1)

Dec 23, 2003

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1187 of the BRCA1 protein (p.Ser1187Asn). This variant is present in population databases (rs80356975, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer and breast cancer and abdominal wall sarcoma (PMID: 21810505, 30287823). This variant is also known as c.3679G>A. ClinVar contains an entry for this variant (Variation ID: 54917). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.16

CADD

Benign

9.6

DANN

Benign

0.97

DEOGEN2

Benign

0.18

T;.;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.1

M;M;.;.

MutationTaster

Benign

0.96

D;D;D;D;D;D;D;D;N;N;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.98

N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.076

T;T;T;T

Sift4G

Benign

0.081

T;T;T;T

Polyphen

0.11

B;.;.;B

Vest4

0.28

MutPred

0.26

Loss of phosphorylation at S1187 (P = 0.0146);Loss of phosphorylation at S1187 (P = 0.0146);.;Loss of phosphorylation at S1187 (P = 0.0146);

MVP

0.69

MPC

0.24

ClinPred

0.14

GERP RS

3.3

Varity_R

0.064

gMVP

0.035

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over