rs273900712

chr17-43091882-A-Gchr17-43091882-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5 BP4_Moderate BP6

The NM_007294.4(BRCA1):c.3649T>C(p.Ser1217Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. S1217C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:4
• Conservation: PhyloP100: 2.38

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 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=0.14779478).
• BP6: Variant 17-43091882-A-G is Benign according to our data. Variant chr17-43091882-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54953.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3649T>C	p.Ser1217Pro	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3649T>C	p.Ser1217Pro	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251312 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.0000385 AC XY: 28 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000105 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 17, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 19, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 2023	The p.S1217P variant (also known as c.3649T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 3649. The serine at codon 1217 is replaced by proline, an amino acid with similar properties. This variant has been reported in both controls and cases from several cancer cohorts, including breast, ovarian, and pancreatic cancer cohorts (Sugano K et al, Cancer Sci. 2008 Oct; 99(10):1967-76; Stegel V et al, BMC Med. Genet. 2011; 12:9; Axilbund JE et al, Cancer Biol. Ther. 2009 Jan; 8(2):131-5; Zhen DB et al. Genet Med, 2015 Jul;17:569-77; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Momozawa Y et al. Nat Commun. 2018 10;9(1):4083; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also identified in an individual diagnosed with an adrenal cortical carcinoma (Owen DH et al. Horm Cancer, 2019 Dec;10:161-167). This alteration, which changes a predicted consensus phosphorylation motif, abolished the ability of BRCA1 to bind CK2/CSNK2A1; however, the clinical significance of this deficit is unknown (Tram E, PLoS ONE 2013 ; 8(5):e62468). Of note, this alteration is also designated as 3768T>C in published literature. This amino acid position is 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. -
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). -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2023	Observed in individuals with breast, ovarian, and/or pancreatic cancer (Sugano et al., 2008; Axilbund et al., 2009; Stegel et al., 2011; Zhen et al., 2015; Azzollini et al., 2016; Wen et al., 2018; Kadri et al., 2020; Andrikopoulou et al., 2022; Zografos et al., 2022); Published functional studies demonstrate abolishment of local CK2A1 and CSNK2A1 binding, preventing phosphorylation of this residue in in vivo studies; however the biological significance of this is not known (Tram et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3768T>C; This variant is associated with the following publications: (PMID: 19016756, 21232165, 19029836, 27062684, 28993434, 25356972, 30287823, 30093976, 32467295, 35127508, 32068069, 33552952, 23704879, 36011273) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 25, 2020	- -

Familial cancer of breast Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 09, 2024	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS1_SUP -
Uncertain significance, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 06, 2023

Variant summary: BRCA1 c.3649T>C (p.Ser1217Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 327244 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (7.9e-05 vs 0.001), allowing no conclusion about variant significance. c.3649T>C has been reported in the literature in individuals affected with Breast or Ovarian Cancer without strong evidence of causality (e.g. Adami_2010, Sugano_2008, Stegel_2011, Azzollini_2016, Wen_2017, Dorling_2021, Momozawa_2018, Kadri_2021, Kwong_2020, Andrikopoulou_2021, Su_2021, Zhang_2022, Zografos_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.5	D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.073	B;.;.;B
Vest4		0.33
MVP		0.76
MPC		0.11
ClinPred		0.054	T
GERP RS		1.4
Varity_R		0.17
gMVP		0.21

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: rs273900712; hg19: chr17-41243899;