17-43045704-G-A

Variant names:

• chr17-43045704-G-A
• rs80357274
• NM_007294.4:c.5566C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM1 BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):​c.5566C>T​(p.Pro1856Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,600 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1856T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:5
• Conservation: PhyloP100: 1.37
• Publications: 15 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: Benign. The variant received -8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 61 uncertain in NM_007294.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.2249012).
• BP6: Variant 17-43045704-G-A is Benign according to our data. Variant chr17-43045704-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 55632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5566C>T	p.Pro1856Ser	missense	Exon 23 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.5632C>T	p.Pro1878Ser	missense	Exon 24 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.5632C>T	p.Pro1878Ser	missense	Exon 24 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5566C>T	p.Pro1856Ser	missense	Exon 23 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5629C>T	p.Pro1877Ser	missense	Exon 24 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5566C>T	p.Pro1856Ser	missense	Exon 23 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250866 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461600 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111838

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 09, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Apr 14, 2015

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.

May 03, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1-related cancer predisposition Benign:1

Mar 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Mar 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20516115, 30257991, 30765603, 28781887, 33552952, 31131967, 17305420, 17453335, 12142080)

Hereditary breast ovarian cancer syndrome Benign:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.95	L
PhyloP100		1.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.43
Sift	Benign	0.28	T
Sift4G	Benign	0.26	T
Polyphen		0.82	P
Vest4		0.077
MVP		0.83
MPC		0.40
ClinPred		0.33	T
GERP RS		1.9
Varity_R		0.090
gMVP		0.18
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs80357274; hg19: chr17-41197721;