rs80357078

Positions:

• chr17-43049162-C-A
• chr17-43049162-C-G
• chr17-43049162-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM5 PP3_Moderate BP6

The NM_007294.4(BRCA1):​c.5365G>T​(p.Ala1789Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A1789G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5 O:1
• Conservation: PhyloP100: 4.31

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 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43049161-GC-T is described in ClinVar as [Pathogenic]. Clinvar id is 462672.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• BP6: Variant 17-43049162-C-A is Benign according to our data. Variant chr17-43049162-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55553.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=3, not_provided=1}. Variant chr17-43049162-C-A is described in Lovd as [Benign]. Variant chr17-43049162-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5365G>T	p.Ala1789Ser	missense_variant	21/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5365G>T	p.Ala1789Ser	missense_variant	21/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 09, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 23, 2003	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 07, 2023	This missense variant replaces alanine with serine at codon 1789 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in transcription activation, homology-directed DNA repair, a haploid cell proliferation and structural stability assays (PMID: 20516115, 29884841, 30209399) and exhibits a moderate decrease in phosphopeptide binding and specificity assays (PMID: 20516115). This variant has been reported in an individual affected with early onset breast cancer with no family history (PMID: 15887246). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.5365G>A (p.Ala1789Thr), has been identified in individuals affected by breast and/or ovarian cancer (PMID: 18680205, 20737206, 30264118, 30287823, Color internal data) and has been reported to impair BRCA1 protein function in several functional studies (PMID: 18680205, 19493677, 20737206, 28781887, 29884841, 30209399, 32546644), suggesting that Ala at this position is important for the protein function. However, the same functional assays, that reported the p.Ala1789Thr variant to be defected, found our variant in question, p.Ala1789Ser, has no impact on BRCA1 function (PMID: 29884841, 30209399). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2023	This missense variant replaces alanine with serine at codon 1789 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant does no impact BRCA1 function in protein stability, phosphopeptide binding and specificity, transcription activation and homology-directed repair assays (PMID: 20516115, 28781887, 30257991) and in a haploid cell proliferation assay (PMID: 30209399) This variant has been reported in an individual affected with early-onset breast cancer with no family history of disease (PMID: 15887246). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.5365G>A (p.Ala1789Thr), has been identified in individuals affected by breast and/or ovarian cancer (PMID: 18680205, 20737206, 30264118, 30287823, Color internal data) and has been reported to impair BRCA1 protein function in several functional studies (PMID: 18680205, 19493677, 20737206, 28781887, 29884841, 30209399, 32546644), suggesting that Ala at this position is important for the protein function. However, the same functional assays, that reported the p.Ala1789Thr variant to be defected, found our variant in question, p.Ala1789Ser, has no impact on BRCA1 function (PMID: 29884841, 30209399). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2021	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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 14, 2019

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Clinvar: LB (VKGL data-share consensus), VUS (Counsyl, Color, BIC - 1 individual). Not in gnomad. Reported in one individual with breast cancer at age 37 (Bonadona 2005). Functional and in silico assays classify variant as not pathogenic (Findlay 2018, Woods 2016, Lee 2010). One in silico study calls variant deleterious as a Serine at this position disrupts the BRCT superfamily conserved G[G/A] motif (Karchin 2008). -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1789 of the BRCA1 protein (p.Ala1789Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 15887246). ClinVar contains an entry for this variant (Variation ID: 55553). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 20516115, 30257991, 30765603). 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	0.26
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N;.;.;.;.;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.036	D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.060	T;D;D;D;D;D;D;T
Polyphen		0.37, 0.98	.;B;.;.;.;D;.;.
Vest4		0.93
MVP		0.96
MPC		0.17
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.66
gMVP		0.78

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: rs80357078; hg19: chr17-41201179;