17-43124087-A-G

Variant names:

• chr17-43124087-A-G
• rs876658707
• NM_007294.4:c.10T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_007294.4(BRCA1):​c.10T>C​(p.Ser4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,846 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S4C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.0880
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 49 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1339649).
• BP6: Variant 17-43124087-A-G is Benign according to our data. Variant chr17-43124087-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 230684.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.10T>C	p.Ser4Pro	missense_variant	Exon 2 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.10T>C	p.Ser4Pro	missense_variant	Exon 2 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460846 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726826

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111156

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Nov 04, 2024

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 proline at codon 4 of the BRCA1 protein. Functional studies have reported the this variant is functionally normal in a haploid cell proliferation assay and in a ubiquitin E3 ligase assay, and it has intermediate activity in a BARD1-binding yeast two-hybrid assay (PMID: 25823446, 30209399). A multifactorial analysis has reported a combined likelihood ratios for pathogenicity of 0.507983 based on segregation and tumor pathology (PMID: 31131967). This variant has not been identified 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. -

May 04, 2019

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. -

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

Mar 04, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Oct 15, 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 proline, which is neutral and non-polar, at codon 4 of the BRCA1 protein (p.Ser4Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 230684). Invitae Evidence Modeling incorporating data from in vitro 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: 30209399). 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. -

not provided Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: PM2, BP1, BP4, BS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.74	T;T;T;T;T;T;T;T;T;T;T;T;T;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.6	L;L;L;L;L;.;.;.;.;.;.;.;.;.
PhyloP100		-0.088
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.020	N;N;N;N;N;N;N;.;N;N;N;D;D;.
REVEL	Uncertain	0.53
Sift	Benign	0.22	T;T;T;D;D;T;T;.;T;T;T;T;T;.
Sift4G	Benign	0.12	T;T;T;T;T;.;T;.;T;.;T;.;.;.
Polyphen		0.38, 0.0010, 0.0030	.;B;.;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.36
MutPred		0.25		Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);Loss of disorder (P = 0.1475);
MVP		0.72
MPC		0.12
ClinPred		0.064	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876658707; hg19: chr17-41276104;