rs397509298

Variant names:

• chr17-43097281-A-C
• rs397509298
• NM_007294.4:c.556T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-43097281-A-C
• chr17-43097281-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_007294.4(BRCA1):​c.556T>G​(p.Ser186Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,192 control chromosomes in the GnomAD database, including 1 homozygotes. 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. S186Y) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (1 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 5.28

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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.556T>G	p.Ser186Ala	missense_variant	Exon 8 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.556T>G	p.Ser186Ala	missense_variant	Exon 8 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250732 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135624

Gnomad AFR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461192 Hom.: 1 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 726924

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: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Nov 09, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of BRCA1-related cancers (de Sanjose 2003, Zuntini 2018, Bahsi 2020); Published functional studies demonstrate reduced ubiquitine ligase activity (Starita 2015); Also known as 675T>G; This variant is associated with the following publications: (PMID: 12845657, 30254663, Bahsi2020[case report], 25823446) -

Jan 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.556T>G (p.Ser186Ala) variant has been reported in the published literature in individuals with breast cancer (PMID: 35409996 (2022), 30254663 (2018), 12845657 (2003)) and colorectal cancer (PMID: 32658311 (2021)). This variant was reported to have a significant effect on BRCA1 E3 ligase activity, however the effect on the full functionality of BRCA1 was not determined (PMID: 25823446 (2015)). The frequency of this variant in the general population, 0.000004 (1/250732 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 11, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 29, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Jul 10, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with alanine at codon 186 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 reported to have examined this variant but the findings were inconclusive (PMID: 25823446, 30219179). This variant has been detected in at least four individuals affected with breast and/or ovarian cancer (PMID: 12845657, 30254663, 35409996; DOI: 10.1515/tjb-2019-0424) and in two individuals affected with colorectal cancer (PMID: 32658311). This variant has been identified in 1/250732 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Dec 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S186A variant (also known as c.556T>G), located in coding exon 7 of the BRCA1 gene, results from a T to G substitution at nucleotide position 556. The serine at codon 186 is replaced by alanine, an amino acid with similar properties. This alteration (designated as 675T>G) was detected in an individual who was diagnosed with breast cancer at 28 and whose father was diagnosed with leukemia at 63 (de Sanjosé S, et al. Int. J. Cancer 2003;106(4):588-93). In addition, this alteration was identified in a family who met a regional protocol for BRCA testing (Zuntini R et al. Front Genet, 2018 Sep;9:378). In another study, this alteration was seen in 0/732 breast cancer patients, 2/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jun 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with alanine at codon 186 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 reported to have examined this variant but the findings were inconclusive (PMID: 25823446, 30219179). This variant has been detected in at least four individuals affected with breast and/or ovarian cancer (PMID: 12845657, 30254663, 35409996; DOI: 10.1515/tjb-2019-0424) and in two individuals affected with colorectal cancer (PMID: 32658311). This variant has been identified in 1/250732 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 186 of the BRCA1 protein (p.Ser186Ala). This variant is present in population databases (rs397509298, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer or ovarian cancer (PMID: 12845657, 35409996). ClinVar contains an entry for this variant (Variation ID: 55633). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 80%. 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. -

Familial cancer of breast Benign:1

Feb 09, 2024

MGZ Medical Genetics Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.;.;.;.;T;.;.;T;.;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.60	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.013	D;D;D;T;D;T;D;D;D;D;D;T;D
Sift4G	Benign	0.69	T;T;T;T;T;T;.;D;T;T;.;T;.
Polyphen		0.97, 0.96, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.
Vest4		0.37
MutPred		0.74		Loss of phosphorylation at S186 (P = 0.0379);Loss of phosphorylation at S186 (P = 0.0379);Loss of phosphorylation at S186 (P = 0.0379);Loss of phosphorylation at S186 (P = 0.0379);.;Loss of phosphorylation at S186 (P = 0.0379);.;.;Loss of phosphorylation at S186 (P = 0.0379);Loss of phosphorylation at S186 (P = 0.0379);.;Loss of phosphorylation at S186 (P = 0.0379);.;
MVP		0.98
MPC		0.26
ClinPred		0.91	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397509298; hg19: chr17-41249298;