17-43092967-T-G

Position:

• chr17-43092967-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BP6

The NM_007294.4(BRCA1):​c.2564A>C​(p.Gln855Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,390 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. Q855K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 2.48

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• BP6: Variant 17-43092967-T-G is Benign according to our data. Variant chr17-43092967-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186203.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2564A>C	p.Gln855Pro	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2564A>C	p.Gln855Pro	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461130 Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2 AN XY: 726772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74392

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 03, 2024	The p.Q855P variant (also known as c.2564A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2564. The glutamine at codon 855 is replaced by proline, an amino acid with similar properties. This alteration was identified in individuals pursuing BRCA1/2 analysis in Japan (Nakamura S et al. Breast Cancer, 2015 Sep;22:462-8; Arai M et al. J Hum Genet, 2018 Apr;63:447-457). This variant has also been identified in breast cancer cohorts as well as unaffected control groups across studies (Momozawa Y et al. Nat Commun, 2018 10;9:4083; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2023	This missense variant replaces glutamine with proline at codon 855 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a suspected hereditary breast and ovarian cancer family and in two individuals affected with breast cancer, in which one of the breast cancer affected individual also has a deleterious BRCA2 mutation (PMID: 11802209, 24249303, 29176636). This variant has been detected in two Japanese breast cancer and prostate cancer case-control studies in 3/7051 female breast cancer cases and 3/11241 unaffected individuals and 3/7636 prostate cancer cases and 5/12366 unaffected individuals (PMID: 30287823, 31214711). This variant also has been detected in a breast cancer case-control meta-analysis and a pancreatic cancer case-control study in which this variant was absent in 60466 breast cancer cases and 1005 pancreatic cancer cases and present in 1/53461 and 8/23705 unaffected individuals in the two respectively studies (PMID: 32980694, 33471991). 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. -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2020	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2683A>C; This variant is associated with the following publications: (PMID: 30287823, 33087888, 29176636, 31131967, 20305393, 24359602, 11802209, 24249303) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 25, 2020

Variant summary: BRCA1 c.2564A>C (p.Gln855Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 298848 control chromosomes (gnomAD and publications), predominantly at a frequency of 1.7e-04 within 47462 Japanese controls who were 60 years old or over and did not have past history nor family history of cancers (Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2564A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Meindl 2002, Nakamura 2015, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic BRCA2 variant has been reported (Nakamura_2015; co-occurring variant not specified), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of Likely Benign based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-segregation with disease, breast tumor pathology and bioinformatic predictions; however, no specific data was provided for independent assessment. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional data of clinical and/or functional importance becomes available. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.4	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.83
MutPred		0.68		Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);.;Gain of loop (P = 0.0502);
MVP		0.94
MPC		0.50
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.56

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: rs768001441; hg19: chr17-41244984;